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Precise combination therapy, involving multiple chemotherapeutics with pharmacologically synergistic antitumor effects, is a promising approach to address the challenge of monotherapy with insufficient activity towards their targets of interest. We employed Pt←pyridine coordination-driven assembly to construct a stoichiometric coordination complex of camptothecin and organoplatinum (II) (Pt-CPT). The Pt-CPT complex exhibited a remarkable synergistic effect toward several tumor cell lines, which is equal to the optimal synergistic effect of (PEt 3) 2 Pt(OTf) 2 (Pt) and CPT mixture at various ratios. An amphiphilic polymer with H 2 O 2 -responsiveness and glutathione (GSH)-depleting ability (PO) was used to encapsulate Pt-CPT complex to enable the nanomedicine (Pt-CPT@PO) with prolonged blood circulation and elevated tumor accumulation. The Pt-CPT@PO nanomedicine exhibited remarkable synergistic antitumor efficacy and antimetastatic effect on a mice orthotopic breast tumor model. This work demonstrated the potential of stoichiometric coordination-driven assembly of organic therapeutics with metal-based drugs in developing advanced nanomedicine with optimal synergistic antitumor activity. In this study, for the first time, we employed Pt←pyridine coordination-driven assembly to construct a stoichiometric coordination complex of camptothecin and organoplatinum (II) (Pt-CPT), with an optimal synergistic effect at various ratios. Then it was encapsulated into an amphiphilic polymer with H 2 O 2 -responsiveness and glutathione (GSH)-depleting ability (PO) to enable the nanomedicine (Pt-CPT@PO) with prolonged blood circulation and elevated tumor accumulation. The Pt-CPT@PO nanomedicine exhibited remarkable synergistic antitumor efficacy and antimetastatic effect on a mice orthotopic breast tumor model. [Display omitted] [ABSTRACT FROM AUTHOR]

Two new copper(II) complexes [Cu(Boc–glycine)(2,2–bipyridyl) 2 ]NO 3 1 and [Cu(Boc–glycine)(1,10–phenanthroline) 2 ]NO 3 2 were prepared, and thoroughly characterized by multiple spectroscopic methods and SC X–ray diffraction studies. pBR322 plasmid DNA cleavage studies showed that the complexes induced single–strand cleavage of DNA at a low concentration of 20 µM and 15 µM which mediated via an oxidative mechanism. SOD memetic activity of the complexes was investigated by using NBT assay which confirmed the superoxide ion scavenging ability of 1. The cytotoxicity activity of complexes was evaluated against MCF–7, PC–3, and HCT–116 cancer cells and the complexes displayed exceptionally good cytotoxic response. [Display omitted] Two new copper(II) complexes [Cu(Boc–glycine)(2,2–bipyridyl) 2 ]NO 3 1 and [Cu(Boc–glycine)(1,10–phenanthroline) 2 ]NO 3 2 were prepared, and thoroughly characterized by multiple spectroscopic methods. The SC X–ray diffraction studies revealed that the complexes crystallized in triclinic (P 1 ¯) system with distorted square pyramidal and octahedral geometry in 1 and 2 , respectively. To predict the anticancer potential of the drug candidates 1 and 2 , binding studies with the ct–DNA were performed by using various complimentary biophysical methods. The drug candidates 1 and 2 interact strongly with DNA exhibiting 'hypochromic' effect in the absorbance bands at 300 nm implicating non–covalent intercalation binding mode that could be induced by the presence of strong recognition domain ligand (phen) which is known to 'wedge–in' in-between the bases of DNA helix. The intrinsic binding constant, K b values were quantified by employing Wolfe–Shimer equation, and were found to be 0.10(±0.14) × 105 M−1 and 1.53 × 106(±0.1) M−1, respectively, showing higher binding propensity of 2 as compared to 1. pBR322 plasmid DNA cleavage studies of the complexes 1 and 2 showed that the complexes induced single–strand cleavage of DNA at a low concentration of 20 µM and 15 µM which mediated via an oxidative mechanism. The cytotoxicity activity of complexes was evaluated against MCF–7, PC–3, and HCT–116 cancer cells and the complexes displayed exceptionally good cytotoxicity against the tested cell lines (1 , HCT–116:IC 50 = 0.6 ± 0.02 μM and 2 , MCF–7:IC 50 = 1.91 ± 0.1 μM). [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.Methods: AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 3200 mg/m2 fluorouracil as a 48 h infusion) plus bevacizumab (5 mg/kg intravenously), and the atezolizumab group received the same regimen plus atezolizumab (840 mg intravenously). Combination treatments were administered up to eight 14-day cycles followed by maintenance with fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to randomisation group, until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint was progression-free survival, analysed by the intention-to-treat principle. Safety was assessed in patients who received at least one dose of the study treatment. The study recruitment is completed. The trial is registered with Clinicaltrials.gov, NCT03721653.Findings: Between Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group.Interpretation: The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer.Funding: GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche. [ABSTRACT FROM AUTHOR]

Objective: Human papilloma virus-negative oropharyngeal cancer has not achieved satisfactory outcomes compared with those of human papilloma virus-positive oropharyngeal cancer. This study evaluated the therapeutic efficacy of selective intraarterial chemoradiotherapy with the docetaxel and nedaplatin regimen for human papilloma virus-negative oropharyngeal cancer.Methods: Twenty-two consecutive patients with human papilloma virus-negative oropharyngeal cancer who had undergone selective intraarterial chemoradiotherapy were retrospectively analyzed. The primary tumor and whole neck were irradiated (50 Gy). Subsequently, the primary site and metastatic lymph nodes were boosted by 20 Gy. The intraarterial chemotherapy regimen comprised a combination of nedaplatin (80 mg/m2) and docetaxel (60 mg/m2), which was initially administered at the start of radiotherapy and was given every 4 weeks for three sessions. Each intraarterial dose of an anticancer agent was determined according to the percentage of the tumor volume supplied by the target artery to the total tumor volume, which was intraoperatively measured via cone-beam computed tomography. The outcome measures were locoregional control, disease-free survival, and overall survival rates and adverse events. Statistical analyses were performed using the Kaplan-Meier method.Results: The median follow-up period was 59 (range, 15-103) months. The T stage was T1/T2 in 5 patients (23%), T3 in 5 patients (23%), and T4 in 12 patients (54%). Cervical lymph node metastasis was staged as ≥N2c in 7 (32%) patients. Complete response was achieved in all patients at the first imaging examination after intraarterial chemoradiotherapy. The 5-year locoregional control, disease-free survival, and overall survival rates were 96% (95% confidence interval, 0.72-0.99), 91% (95% confidence interval, 0.68-0.98), and 100% (95% confidence interval, not available), respectively. Regarding serious acute adverse events, grade 4 laryngeal edema and leukopenia were observed in 1 (5%) and 11 patients (50%), respectively. No other serious acute adverse events were observed.Conclusion: Selective intraarterial chemoradiotherapy with docetaxel and nedaplatin has the potential to achieve favorable locoregional control, disease-free survival, and overall survival rates in human papilloma virus-negative oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

• Aroylhydrazone-based dioxidomolybdenum(VI) complex was synthesized. • Structure elucidation of aroylhydrazone and Mo(VI) complex by single crystal X-ray diffraction. • Mo center adopts a distorted octahedral geometry. • Mo(VI) complex functions as a catalyst in the cyclooctene epoxidation. • Mo(VI) complex displayed a 97 % yield of cyclooctene epoxide. A dioxidomolybdenum(VI) complex, [MoO 2 (SMBH)(DMSO)] derived from tridentate ONO aroylhydrazone, salicylaldehyde-3-methoxybenzhydrazone (SMBH 2), has been synthesized. The investigation of the structural characteristics of both aroylhydrazone and its molybdenum(VI) complex were conducted using various spectroscopic techniques (FT-IR, UV–Vis, 1H NMR, MS) and analytical methods (elemental and single crystal XRD analysis). The molecular structures of the aroylhydrazone and molybdenum(VI) complex were confirmed through single-crystal X-ray diffraction (XRD) studies. The presence of the amido form of the aroylhydrazone in the solid state was corroborated through IR spectroscopy and single-crystal XRD. The aroylhydrazone, salicylaldehyde-3-methoxybenzhydrazone (SMBH 2), and its Mo(VI) complex got crystallized in monoclinic space group P 2 1 /c and triclinic space group P 1 ‾ respectively. The molybdenum complex exhibits a distorted octahedral geometry, with the aroylhydrazone serving as a bi-anionic tridentate donor ligand. The molybdenum(VI) centre in the complex is coordinated by the aroylhydrazone, two oxido groups, and an oxygen atom from the DMSO solvent. Non-covalent interactions, such as hydrogen bonding, C–H···π interactions, and π···π interactions, contribute to the stabilization of the crystal structures of both the aroylhydrazone and the molybdenum complex. The developed molybdenum complex showed potential as a catalyst for the cyclooctene epoxidation reaction, achieving a conversion of 97 % to produce 1,2-epoxycyclooctane under ambient reaction conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Adjuvant chemotherapy is not recommended for patients with average-risk stage II (T3N0) colon cancer. Nevertheless, a subgroup of these patients who are CDX2-negative might benefit from adjuvant chemotherapy. We evaluated the cost-effectiveness of testing for the absence of CDX2 expression followed by adjuvant chemotherapy (fluorouracil combined with oxaliplatin [FOLFOX]) for patients with stage II colon cancer.Methods: We developed a decision model to simulate a hypothetical cohort of 65-year-old patients with average-risk stage II colon cancer with 7.2% of these patients being CDX2-negative under 2 different interventions: (1) test for the absence of CDX2 expression followed by adjuvant chemotherapy for CDX2-negative patients and (2) no CDX2 testing and no adjuvant chemotherapy for any patient. We derived disease progression parameters, adjuvant chemotherapy effectiveness and utilities from published analyses, and cancer care costs from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Sensitivity analyses were conducted.Results: Testing for CDX2 followed by FOLFOX for CDX2-negative patients had an incremental cost-effectiveness ratio of $5500/quality-adjusted life-years (QALYs) compared with no CDX2 testing and no FOLFOX (6.874 vs 6.838 discounted QALYs and $89 991 vs $89 797 discounted US dollar lifetime costs). In sensitivity analyses, considering a cost-effectiveness threshold of $100 000/QALY, testing for CDX2 followed by FOLFOX on CDX2-negative patients remains cost-effective for hazard ratios of <0.975 of the effectiveness of FOLFOX in CDX2-negative patients in reducing the rate of developing a metastatic recurrence.Conclusions: Testing tumors of patients with stage II colon cancer for CDX2 and administration of adjuvant treatment to the subgroup found CDX2-negative is a cost-effective and high-value management strategy across a broad range of plausible assumptions. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma.Methods: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed.Findings: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported.Interpretation: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma.Funding: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University.Translation: For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer.Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients).Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.Funding: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research. [ABSTRACT FROM AUTHOR]

Hydrogen-evolving cathodes were prepared using a series of iron(ii) clathrochelates bearing various number of terminal phenanthrenyl groups via physisorption on carbon paper and employed in the polymer electrolyte membrane water electrolysis cells instead of typically used platinum. In situ electrochemical activation of the cathodes was carried out, after that the cells performance and durability were evaluated. These clathrochelate complexes represent a promising alternative to platinum as hydrogen-evolving cathode electrocatalysts. [ABSTRACT FROM AUTHOR]

Background: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.Methods: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.Findings: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.Interpretation: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.Funding: AbbVie. [ABSTRACT FROM AUTHOR]

A bicontinuous lamellar silica mordenite (HM@KCC-1) has been successfully synthesized by microemulsion technique assisted with mordenite-seed recrystallization, followed by protonation and impregnation with platinum (Pt). The catalysts were extensively characterized by XRD, N 2 adsorption, FTIR, FESEM, TEM and ESR and the activity was tested in hydroisomerization of n -hexane. Fourier Transform-Infrared Spectroscopy (FT-IR) study through pyridine and 2,6- dimethylpyridine adsorption revealed that Pt/HM@KCC-1 possessed abundant Lewis acid sites and moderate Brønsted acid sites while Pt/HM possessed strong Lewis and Brønsted acid sites. At 300 °C, the conversion of n -hexane on Pt//HM@KCC-1 reached 75% with 98% isomer selectivity and 74% isomer yield. The enhancement of catalytic performance is attributed to the well-dispersed Pt nanoparticles, tuned acidic properties and improved textural properties which provided a well balance in the acid/metal functions. Thus, favours the reaction towards higher hydroisomerization selectivity, limiting the undesired consecutive cracking reaction. Image 1 • HM@KCC-1 was synthesized via a microemulsion mordenite seed-crystallization system. • HM@KCC-1 possessed high surface area with bicontinuous lamellar silica (KCC-1) morphology. • Moderate Brønsted acid sites on Pt/HM@KCC-1 favoured hydroisomerization. • Pt/HM@KCC-1 showed good Pt dispersion and no diffusional limitation. • Pt/HM@KCC-1 gave the highest isomer yield of 74% at 300 °C. [ABSTRACT FROM AUTHOR]

[Display omitted] • Series of new Pt(II) complexes with sulfonylthiourea ligands synthesised. • Ligand shows preferential distal isomer formation (Pt-NR) with the NSO2R nitrogen uncoordinated. • Computational investigations of non-covalent interactions reveal chalcogen bonding. A series of sulfonyl-substituted thiourea platinum(II) complexes bearing ancillary phosphine ligands were prepared by the reaction between cis -[PtCl 2 (PR 3) 2 ] (PR 3 = triphenylphosphine, tris(2-cyanoethyl)phosphine and 1,3,5-triaza-7-phosphaadamantane) and either p -TolSO 2 NHC(S)NHPh or EtSO 2 NHC(S)NHPh, in a refluxing Et 3 N/methanol mixture. The mixed ligand complexes, bearing a single phosphine and pyridine, were also prepared by the reactions between cis -[PtCl 2 (COD)] (COD = cyclooctadiene), pyridine and p -TolSO 2 NHC(S)NHPh or EtSO 2 NHC(S)NHPh. For each complex, the thiourea ligand binds as a dianion through the S and NPh groups in the distal isomer with a remote NSO 2 R group. Only in the case of the reaction between the complex cis -[PtCl 2 (PPh 3) 2 ] and TolSO 2 NHC(S)NHCH(CH 3) 3) was the proximal isomer formed on account of the bulky t -butyl substituent on the thiourea. X-ray structures and computational analysis revealed another reason for this preferential distal isomer formation is most likely due to the presence of a stabilising chalcogen bond, which is otherwise unavailable in the proximal isomer. [ABSTRACT FROM AUTHOR]

• Synthesis of new organo-selenate compounds, B4-CASeO 4 ·3H 2 O and B4-CASeO 4. • Calculation and quantitatively analysis of intermolecular interaction topology. • For the hydrogen bonded anion-cation pairs very high values of interaction energies were obtained. • HS fingerprint plots, indicate similar type of interactions with different intensity. • Compounds were found to have antioxidant, antibacterial and antifungal activities. Two new organo-selenate compounds, bis(4-carboxyanilinium) selenate trihydrate (B4-CASeO 4 ·3H 2 O) and bis(4-carboxyanilinium) selenate (B4-CASeO 4) were synthesized and it was found to have antioxidant, antibacterial and antifungal activities. These crystals were characterized by single-crystal X-ray diffraction, DSC, IR spectroscopy and computational analysis. B4-CASeO 4 ·3H 2 O crystallizes in the triclinic space group, P -1, Z = 2 and B4-CASeO 4 crystallizes in the monoclinic space group, P2 1 /c, Z = 4. Both crystal structures consist of organic and inorganic layers which are interlinked by ionic and extensive N—H....O hydrogen-bonding interactions, between the NH 3 + group of the cation and O-atom of anion. Such an extensive three dimensional hydrogen-bonding framework stabilize the crystal structure. In B4-CASeO 4 crystal the cation, 4-CA exists as a dimer due to strong O H···O hydrogen bonding interaction. Such dimer formation is not observed in B4-CASeO 4 ·3H 2 O. The fingerprint plots obtained using CrystalExplorer21 indicated that, the most prominent interaction in both crystals corresponds to the short O···H contacts and also the other interactions were similar. However their values were different indicating the intermolecular interactions were quite different. The intermolecular interaction topology of B4-CASeO 4 ·3H 2 O and B4-CASeO 4 has been quantitatively analyzed using the computational tool of energy framework analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

• Detail study of (η6-C 6 Me 6)Ru(Cl) 2 (P(OMe) 3) with AgOTf in different solvents. • A comparative study of counterions OTf− and BF 4 −in [(η6-C 6 Me 6)Ru(Cl)(P(OMe) 3) 2 ]X. • Formation of mono-, di- and trinuclear structures with (η6-C 6 Me 6)Ru(P(OMe) 3) moieties. • Complex sequence which undergoes coordinated trimethylphosphite ligands in solution. • A great preference to coordinate adventitious water and labile acetone adducts. An extensive study of the reactions of (η6-C 6 Me 6)Ru(Cl) 2 (P(OMe) 3) (1) with AgOTf in three different deuterated and non-deuterated solvents: chloroform, acetone and nitromethane is described. A series of compounds with the moiety (η6-C 6 Me 6)Ru(P(OMe) 3) is isolated and characterized, along with their crystalline structures. A simple associative step assisted by coordination of the silver cation to two molecules of 1 through the Cl-Ru-Cl bonds affords [{(η6-C 6 Me 6)Ru(Cl) 2 (P(OMe) 3)} 2 (μ-Ag)](OTf) (2), loss of AgCl from 2 gives 1 and (η6-C 6 Me 6)RuCl(OTf)(P(OMe) 3) (3), meanwhile 3 dimerizes to [(η6-C 6 Me 6)Ru(μ-Cl)(P(OMe) 3)] 2 (OTf) 2 (4) which in presence of P(OMe) 3 gives [(η6-C 6 Me 6)RuCl(P(OMe) 3) 2 ](OTf) (11OTf). A comparative study of the influence of the counterions OTf− and BF 4 − was carried out with the analogue [(η6-C 6 Me 6)RuCl(P(OMe) 3) 2 ](BF 4) (11BF4), as well as the corresponding demethylation of the coordinated trimethylphosphite ligands by the classical Michaelis-Arbuzov reactions. The resulting "quasi-chelate" (η6-C 6 Me 6)RuCl(P(O)(OMe) 2)(P(OH)(OMe) 2) (17) where a bridging proton in the phosphinito-phosphinous acid ligands is replaced by BF 2 affords (η6 - C 6 Me 6)RuCl({P(OMe) 2 (O)} 2 BF 2) (18) which contains the chelating structure [Me 2 POBF 2 OPMe 2 ]. The chemistry in solution at room temperature of 1 with AgOTf shows non-selective reactions, as can be determined by multinuclear NMR spectroscopy (1H, 13C{1H}, 31P, 19F). The mixture of products shows a great preference to coordinate water, even when it is in traces, as observed for the formation of [(η6-C 6 Me 6)RuCl(H 2 O)(P(OMe) 3)](OTf) (5), [(η6-C 6 Me 6)Ru(H 2 O)(OTf)(P(OMe) 3)]OTf (6) and [(η6-C 6 Me 6)Ru(H 2 O) 2 (P(OMe) 3)](OTf) 2 (7), being the latter 7 the "sink" product. Also, in presence of anhydrous AgOTf compound 1 can be transformed into the highly hygroscopic (η6-C 6 Me 6)Ru(OTf) 2 (P(OMe) 3) (8) which readily replaces triflate ligands by trace water. Structural characterization by single crystal X-ray diffraction of trinuclear compound 2 , dinuclear 4 and mononuclear 7, 11X (X = OTf, BF4), 18 and nitrile derivatives [(η6-C 6 Me 6)Ru(NCR) 2 (P(OMe) 3)](OTf) 2 (R = Et, 9 ; Me, 10) is discussed. The chemical transformations of AgOTf with (η6-C 6 Me 6)Ru(Cl) 2 (P(OMe) 3) lead to a variety of organoruthenium compounds in a non-selective path. The competition between products depends on the stoichiometry, solvent, and largely on the silver triflate salt, whose hygroscopic capacity favors the coordination of water in several compounds under study. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The crystal systems and space groups from the crystals gave complexes 2 (triclinic, P-1) and 3 (monoclinic, P1 21/c1) • DFT calculation by B3LYP/LanL2DZ method, FMOs and NBO analyses. • The complexes have more distinct activity than the ligand against bacteria strains. • Binding affinity showed the complexes significantly bind to S. aureus tyrosyl-tRNA synthetase. Two Schiff base complexes, namely Ni(L1)(NCS) 2 (2) and Cu(L1)(NCS).SCN (3) (where L1 = [ N,N ′-bis(1-(pyridin-2-yl)ethylidene)propane-1,3-diamine]) have been synthesized through condensation of L1 with metal acetates using a 2:1 ratio, in the presence of sodium thiocyanate, NaSCN. The complexes were characterized by elemental analysis, IR, UV–Vis, magnetic moment, as well as molar conductivity. The crystal structures of complexes 2 and 3 were successfully characterized by single crystal X-ray crystallography. The Ni atom in 2 is in a distorted octahedral environment while the Cu atom in 3 is in an environment lying between square pyramidal and trigonal bipyramidal; in both complexes the NCS− is acting as terminal ligand. Both complexes were paramagnetic. Density functional theory (DFT) calculations were performed at the B3LYP/LanL2DZ level of theory to explore the quantum chemical properties of the ligand and its metal complexes. The calculations proceed with the 3D crystal structure characterization of the complexes, and the correlation between theoretical and experimental results were discussed. NBO analysis was used to determine the strength of donor–acceptor interactions in metal complexes. The antibacterial activity of the synthesized compounds was screened in vitro against two strains of Gram-positive (Staphylococcus (S.) aureus, Staphylococcus (S.) haemolyticus) and three strains of Gram-negative (Shigella (S.) sonnei, Salmonella (S.) typhimurium, Enterobacter (E.) aerogenes) bacteria, and showed no activity. The binding affinity of the synthesized complexes in the binding site of S. aureus tyrosyl-tRNA was investigated using molecular docking, and the outcomes showed a good agreement with experimental results. [ABSTRACT FROM AUTHOR]

N -heterocyclic carbene (NHC) based compounds are remarkably known for astonishing biological potentials. Coordination of metal center with these compounds can substantially improve the biological potential for better efficacy. In this context, three binuclear azolium salts (L1-L3) and subsequent selenium adducts L1Se-L3Se were synthesized and assured through analytical techniques. Synthesized compounds were also simulated through computational approach and results were compared with experimental observations that also relatable with biological potentials. Synthesized compounds were screened against bacterial strains and interestingly, the studied compounds showed good antimicrobial potential with MIC values of 7.01, 10.7 and 10.5 µM for S. Aureus (gram positive bacteria) while 12.5, 11.75 and 14.5 µM against E. Coli (gram negative bacteria). The studied compounds showed good antioxidant activity to scavenge DPPH free radicals among which azolium salts were found better in antioxidant potential (IC 50 5.75–6.55 µg/mL) than their respective selenium compounds (IC 50 9.50–12.75 µg/mL). The hemolytic assay against red blood cells showed that ligands are least toxic comparative to their Se-adducts and can be further trialed for In Vivo studies. [Display omitted] • To synthesize new benzimidazolium based stable bi-nuclear ligands and their Se-NHC compounds. • To check mutagenic or non-mutagenic potential of the synthesized compounds by Ames assay. • Computational and molecular docking studies of the compounds. • To find the various biological activities including antibacterial, biofilm inhibition, DPPH and hemolytic activity. [ABSTRACT FROM AUTHOR]

The binuclear platinum(IV) complexes [NBu 4 ] 2 [PtIV 2 (μ-Cl) 2 (C 6 F 5) 4 Cl 4 ] (2) and [PtIV 2 (μ-C 8 H 6 N 4) 2 (C 6 F 5) 4 Cl 4 ] (4) have been synthesized by oxidative addition of chlorine to the binuclear platinum(II) species, but [NBu 4 ] 2 [PtIV 2 (μ-OH) 2 (C 6 F 5) 4 Cl 4 ] (3) has been synthesized by substitution of the chloride bridges of the platinum(IV) complex. The square planar platinum environments of the Pt(II) starting materials change, as expected, to Pt(IV) octahedral environments with the chloride ligands in trans -position. Only minor changes in the Pt-X (X = Cl bridge , OH) interatomic distances are produced because of the oxidation. Depending on the size of the bridging ligands and also probably the anionic character of the diplatinum(IV) complexes, the apical chloride ligands can still act as bridges toward other Pt centers. Thus, the organometallic tetra-nuclear mixed-valence platinum(IV)-platinum(II) complexes with formulas [NBu 4 ] 2 [{PtIV(μ-X)(C 6 F 5) 2 } 2 (μ-Cl) 4 {PtII(C 6 F 5) 2 } 2 ] [X = Cl (5), OH (6)] were obtained by reaction of 2 and 3 with cis -[PtII(C 6 F 5) 2 (thf) 2 ]. The structures of complexes 2 , 4 and 6 have been determined by single-crystal X-ray diffraction studies. These crystal structures confirm that the oxidative addition of the chlorine molecule to the platinum(II) complexes 2 and 3 takes place on the axial positions of the platinum centers suggesting a SN 2 mechanism. On the other hand, the central core of the anion of 6 has a chair like conformation and the long Pt⋯Pt distances (>3.2 Å) clearly exclude any Pt.···Pt interaction. On the other hand, cis -[(C 6 F 5) 2 Pt(μ-C 8 H 6 N 4)Pt(C 6 F 5) 2 ] (1) can be reduced either electrochemically or by reacting with [CoCp 2 ] to the anion [Pt 2 (μ-C 8 H 6 N 4)(C 6 F 5) 4 ]- which in the last case, can be isolated as complex 7. According to the EPR studies the anion is not a mixed Pt(II)/Pt(I) compound but a binuclear Pt(II) derivative with the anion [C 8 H 6 N 4 ]- as bridging ligand. Image 1 • Tetranuclear organometallic mixed valence Pt(II)/Pt(IV) complexes are synthesized. • Axial halogenide ligands of binuclear Pt(IV) derivatives bridge Pt(II) complexes. • Oxidation of binuclear Pt(II) complexes render binuclear Pt(IV) derivatives. • Binuclear Pt(IV) derivatives may form mixed valence Pt(II)/Pt(IV) complexes. [ABSTRACT FROM AUTHOR]

Purpose: The ongoing phase 2/3 PRODIGE 26/CONCORDE trial compares chemoradiation therapy with and without dose escalation in patients with locally advanced or unresectable esophageal cancer. The results of a benchmark case procedure are reported here to evaluate the protocol compliance of participating centers as part of quality assurance for radiation therapy.Methods and Materials: Volume delineation, target coverage, and dose constraints to the organs at risk (OARs) were assessed on treatment plans of a common benchmark case performed by each participating center. The centers were classified in 3 categories: per protocol, minor acceptable deviation (MiD), or major unacceptable deviation (MaD). A plan was rejected if ≥4 MiDs or 1 MaD were found.Results: Thirty-5 centers submitted 43 plans. Among them, 14 (32.6%) were per protocol, 19 (44.2%) presented at least 1 MiD, 2 (4.6%) presented at least 1 MaD, and 8 (18.6%) presented both MiD and MaD. Overall, 11 (25.6%) plans were rejected. Only 1 plan was rejected because gross tumor volume was not correctly delineated. The OAR delineation was respected in all cases. Dose constraints to the OARs were respected in the majority of cases except for the heart, where one-third of the plans presented a deviation. As for the target volume, 3 plans (5.8%) had a major underdosage and 1 plan (1.9%) had a major overdosage. Overall, 58% of all treatments were planned with intensity modulated radiation therapy, whereas 42% were planned with 3-dimensional chemoradiation therapy. Significantly more plans in the intensity modulated radiation therapy group were accepted compared with the 3-dimensional chemoradiation therapy group (P = .03).Conclusion: The high frequency of protocol deviations underlines the importance of a quality assurance program in clinical trials. Further work should assess the impact of quality assurance for radiation therapy on patient outcomes. [ABSTRACT FROM AUTHOR]

N -Aryl- N ′, N ″-di(pyridin-2-yl)- and N -aryl- N ′, N ″-bis(6-methylpyridin-2-yl)guanidines (1 – 4 and 5 – 7) were isolated in 75%–81% yields. Reactions of Pd(OAc) 2 with guanidines 2 – 7 carried out separately in toluene at 60 °C for 3 h afforded 8 – 13 respectively in 69%–80% yields. Compounds 1 – 13 were characterized by elemental analyses, HR-MS, IR and NMR (1H and 13C) spectroscopy. Molecular structures of guanidines 1 , 4 , 5 and 6 and those of 8 – 13 were determined by single crystal X-ray diffraction. The Pd(II) atom in 8 – 10 revealed trans geometry while that in 11 – 13 revealed cis geometry. DFT calculations were carried out on model compounds 9a (trans) and its hypothetical cis isomer, 9b and 12a (cis) and its hypothetical trans isomer 12b which indicated a very small energy difference between the 9a / 9b pair (1.28 kcal/mol) whereas a large energy difference was observed between the 12a / 12b pair (26.38 kcal/mol) in CH 2 Cl 2. The catalytic utility of 9 in Heck-Mizoroki coupling reactions involving styrene and methyl acrylate and aryl bromides/aryl chlorides in the presence of NaOAc and excess of tetrabutylammonium bromide (TBAB) at 120 °C was explored. Both activated and de-activated aryl bromides and aryl chlorides were coupled with styrene and in addition, the aryl chlorides were coupled with methyl acrylate in the presence of 9 to afford the respective coupling products in 68% − >99% yields. Neat reaction carried out with 9 and TBAB under the optimized condition released the colloidal Pd black as verified by EDAX, PXRD and SEM techniques thereby implying the heterogeneous nature of catalysis. The reaction of less hindered guanidine 3 with Pd(OAc) 2 in toluene at 60 °C afforded 9 while the analogous reaction with more hindered guanidine 6 afforded 12. Energetics of 9 and 12 and their geometric counterparts have been studied by DFT calculations. The utility of 9 as catalyst in Heck-Mizoroki coupling reactions was explored. Image 1 • Pyridyl and 6-methyl pyridyl based unsymmetrical guanidines were isolated and structurally characterized. • Cis and trans homoleptic Pd(II) guanidinato complexes were prepared and structurally characterized. • Steric factor forces cis isomer formation as shown by DFT calculations. • The new complexes were shown to be active catalysts in Heck-Mizoriki coupling reactions. [ABSTRACT FROM AUTHOR]

Detailed 1H NMR spectroscopic studies of reactions of hydrolysis products of the antitumor agent Cisplatin with the model nucleobase 1-methyluracil (1MeUH) and its anion (1MeU) reveal that the complex mixture formed ("Pt pyrimidine blues"), once considered potential second generation Pt antitumor drugs, predominantly consists of diamagnetic species of 1:1-, 1:2-, 2:2-, and 2:1 (Pt:1MeU) stoichiometries. Paramagnetic oligomeric species responsible for the color are present in a low-% range only. • "Pt-1-methyluracil blue" is a mixture of dia- and paramagnetic components. • Diamagnetic species have been identified by 1H NMR spectroscopy. • They are of 1:1-, 1:2-, 2:2-, and 1:2-stoichiometries (Pt:1MeU). • They represent by far the majority of species present in this "Pt blue". Antitumor-active "Pt-pyrimidine blues", derived from cis- (NH 3) 2 PtII and the pyrimidine model nucleobase 1-methyluracil (1MeUH) upon reaction in a 1:1-ratio in water, represent mixtures of predominantly (ca. 95%) 1:1-, 1:2-, 2:2-, 2:1- complexes (Pt:1MeU(H)) and unreacted 1MeUH, as well as a minor proportion (estimated 5%) of oligomeric species, some of which become partially oxidized to provide the blue color. The present study concentrates on the identification of (at least) seven colorless or yellow diamagnetic components by use of 1H NMR spectroscopic methods (1H, 1H-COSY; DOSY) and/or by comparison with isolated authentic samples, respectively. These are cis -[Pt(NH 3) 2 (1MeU- N3)(OH 2)]+ (1b), cis -Pt(NH 3) 2 (1MeU- N3) 2 (1c), head - tail- and head-head isomers of cis- [(NH 3) 2 Pt(1MeU- N3,O4) 2 Pt(NH 3) 2 ]2+ (3a) and (3b), respectively, cis- [(NH 3) 2 Pt(µ-OH)(µ-1MeU- N3,O4) Pt(NH 3) 2 ]2+ (10), cis- [(NH 3) 2 (1MeU- N3)Pt (µ-OH)Pt(1MeU- N3)(NH 3) 2 ]+(4), and unreacted 1MeUH. A likely eights component, cis- [(NH 3) 2 (1MeU- N3)Pt(µ-OH)Pt(OH/OH 2)(NH 3) 2 ]+/2+ (9) has not been identified unambiguously. The propensities of PtII to form µ-hydroxido species and of N3-platinated 1MeU to attract a second PtII via its O4 site are responsible for the formation of these species. The as yet unidentified minor, presumably oligomeric species most likely represent compounds with terminal 1MeU- N3 ligands, as well as bridging 1MeU- N3,O4 and/or bridging OH− ligands, formed upon co-condensation reactions of primary products with available cis- [Pt(NH 3) 2 (OH 2) 2 ]2+. Earlier ideas, that "Pt-pyrimidine blues" may largely or even exclusively be oligomers with a uniform motif involving exclusively bridging pyrimidine ligands, are not substantiated by our study. [ABSTRACT FROM AUTHOR]

• Heterobimetallic [PtM(SAc) 4 (L)] lantern complexes containing divalent Mn, Fe, Co, Ni, and Zn. • Exceptionally long Pt⋯Pt contacts for [PtM(SAc) 4 (pySMe)] with M = Fe, Co, Ni. • Antiferromagnetic coupling observed between [PtM(SAc) 4 (pySMe)] dimers. A new series of heterobimetallic lantern complexes, [PtM(SAc) 4 (pySMe)] (M = Mn (1), Fe (2), Co (3), Ni (4), Zn (5)), as well as additions to the previously reported series, [PtM(SAc) 4 (pyNH 2)] (M = Mn (6), Fe (7)), have been synthesized and thoroughly characterized. Notably, compounds 1 and 6 are the first crystallographically characterized, neutral Pt-Mn containing lantern complexes. Compounds 2 and 7 are the first examples of Pt-Fe containing lantern complexes with a pyridine based axial ligand. These newly synthesized complexes have been characterized by single-crystal X-ray diffraction and UV–vis (1 – 7), 1H and 13C NMR spectroscopies (5), and solution magnetic susceptibility (1 – 4 and 6 – 7) and analyzed in comparison to our previously reported lantern families. Compounds 2 – 4 are isomorphous and contain two crystallographically independent dimers with the same staggered conformations. One dimer has a typical Pt⋯Pt metallophilic interaction ranging from 3.2198(6) to 3.2913(6) Å while the other has a much longer contact ranging from 3.3212(6) to 3.4533(6) Å. These latter contacts suggest metallophilic interactions that are the longest reported to date in any system. Solid state variable-temperature magnetic susceptibility studies suggest antiferromagnetic coupling between the 3 d metal centers in the two lantern complexes of the dimeric forms of 2 , 3 , and 4. [ABSTRACT FROM AUTHOR]

A luminescent butterfly-shaped dinuclear Pt(II) complex having pyridyl-NHC chelate ligands and bridging Me 2 pz ligands was synthesized. The crystal structure showed unique packing structure containing one-dimensional infinite pore that was filled with solvent molecules. • A butterfly-shaped Pt 2 complex having Py-NHC ligands showed bluish-green emission. • The crystal showed unique packing structure with one-dimensional infinite pore. • The lowest-energy absorption bands were investigated using TD-DFT method. A butterfly-shaped dinuclear Pt(II) complex having pyridyl-NHC chelate ligands and bridging Me 2 pz ligands was synthesized. The crystal structure of the Pt 2 complex showed short intramolecular Pt⋯Pt distance (3.129 Å) and unique packing structure containing one-dimensional infinite pore that was filled with solvent molecules. The absorbance was proportional to the concentration of Pt 2 complex and no significant bands appeared even in high concentration (up to 100 μM). The Pt 2 complex showed bluish-green emission (λ max = 459 nm) in the solid state at 298 K (λ ex = 330 nm). TD-DFT calculation revealed that the lowest-energy absorption bands are mainly assigned to the combination of metal-to-ligand charge transfer (MLCT) and ligand-to-ligand charge transfer (LLCT) transitions. [ABSTRACT FROM AUTHOR]

• Modeling studies of capsular complexes of resorcin[4]arene tetraesters presented. • Their molecular mechanics studies with two force fields gave conflicting results. • Molecular dynamics with included Mulliken atomic charges gave the correct trend. • Density-functional solvent model gave the correct energetic trend of π–stacking. Dimeric capsular complexes of two C 2V -symmetrical resorcin[4]arene tetraesters with tetramethylammonium cation have been analyzed by a number of theoretical tools to rationalize the experimentally observed preferential formation of heterodimeric complexes over homodimeric ones. These tools range from purely empirical (force fields) to quantum chemical (density-functional theory) approaches. The importance of solvent and thermal effects on the final stabilities of capsular complexes has also been addressed. It has been clearly demonstrated that the quality of results obtained with the empirical force fields improves through the respective molecular dynamics simulations employing Mulliken atomic charges in both gas phase and in a solvent. On the quantum chemical side, density-functional theory calculations including the solvent model based on density (SMD) and thermal corrections resulted in a correct energetic preference of a heterodimeric structure over homodimeric ones. [ABSTRACT FROM AUTHOR]

• Pt(IV) derivatives of oxaliplatin with a redox modulator in axial position were synthesised. • The complexes produce cellular reactive oxygen species (ROS). • The most potent ROS producer elicits the highest cytotoxicity. The coordination of biologically active moieties to the axial positions of Pt(IV) derivatives of Pt(II) anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV) complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV) complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by 1H and 195Pt NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans -[Pt(DACH)(ox)(IPA)(OH)] (1), trans -[Pt(DACH)(ox)(IPA) 2 ] (2), trans -[Pt(DACH)(ox)(IPA)(bz)] (3), trans -[Pt(DACH)(ox)(IPA)(suc)] (4), and trans -[Pt(DACH)(ox)(IPA)(ac)] (5) (DACH = 1,2-diaminocyclohexane (1R,2R)-(−), ox = oxalate, IPA = indole-3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS) in a time-dependent manner. The most potent ROS producer, complex 1 , also elicited the highest cytotoxicity. Complex 1 was shown to form the mono- and bis-adducts [Pt(DACH)(guanosine)(OH)]+ and [Pt(DACH)(guanosine) 2 ]2+ in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA. [ABSTRACT FROM AUTHOR]

• Diaminetetracarboxylatoplatinum(IV) complexes are potential anticancer prodrugs. • Novel complexes exhibited IC 50 values down to the low micromolar range. • Lipophilicity and reduction for two compound series was determined. • Lipophilicity as well as reduction were found to parallel the cytotoxic properties. A series of novel bis(carboxylato)oxalatobis(1-propylamine)platinum(IV) complexes as well as an ethylamine analog were synthesized. The compounds are either symmetrical with both axial ligands consisting of monoesters of succinic acid, or unsymmetrical, with one axial ligand being acetate. The compounds were characterized in detail by elemental analysis, mass spectrometry and multinuclear (1H, 13C, 15N, 195Pt) NMR spectroscopy. The reduction behavior was followed by NMR spectroscopy, while lipophilicity was determined by analytical reversed-phase HPLC measurements. The capacity of inhibiting proliferation of the human cancer cell lines A549 (non-small cell lung cancer), CH1(PA-1) (ovarian teratocarcinoma) and SW480 (colon carcinoma) was evaluated by the MTT assay. In the most sensitive cell line CH1(PA-1), all compounds exhibited IC 50 values in the lower µM range. In general, the IC 50 values decreased with increasing lipophilicity within the two compound series. Nevertheless, replacing one of the succinic ester ligands with acetate has a rather marginal impact on antiproliferative activity and is hardly disadvantageous. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Platinum complex. • Crystal structure. • Neuritogenic activity. Abstract A novel mononuclear platinum complex with N 2 O 2 donor atoms was synthesized from the ligand, [N,N′-bis(3-methoxysalicylidene)-2,2-dimethylpropane-1,3-diamine], H2L. The complex was characterized by microanalysis (C, H, N), spectroscopic studies and single crystal X-ray crystallography. The TGA study revealed that the complex degraded in two distinct steps. The effect of the platinum complex was examined by exposing the synthesized complex to rat embryonic hippocampal neurons. The results exhibited significant neuritogenesis at low doses, suggesting it to be a potential therapeutic candidate for combating the neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract The first examples of adenine binding by isomeric organoplatinum(II) complexes bearing H-bonding nicotinic and isonicotinic acid ligands are reported. Notably, a subtle switching of the H-bonding functionality from the 3- to 4-position of the pyridyl ring leads to a significant change in both the strength of association and the site of adenine binding. Graphical abstract The first examples of adenine binding by isomeric organoplatinum(II) complexes bearing H-bonding nicotinic and isonicotinic acid ligands are reported. Image 1 Highlights • The first examples of non-covalent binding to adenine by organoplatinum(II) complexes are reported. • A switching of the H-bonding group leads to a significant change in both the strength and site of adenine binding. • The nicotinic acid derivative strongly H-bonds to the Watson Crick-site of 9-sec-pentyladenine (9-PA) in CDCl 3 solution. • Conversely, the isonicotinic acid derivative H-bonds to the Hoogsteen site of 9-PA and the binding interaction is limited. [ABSTRACT FROM AUTHOR]

Abstract Two hetero-trinuclear complexes of the type [Eu(btfa) 3 Pt 2 -bpy] and [Eu(nta) 3 Pt 2 -bpy] (where btfa and nta is the anion of 4,4,4-trifluoro-1-phenyl-1,3-butanedione; 4,4,4-trifluoro-1-(2-naphthyl)-1,3-butanedione, respectively and Pt 2 bpy = trans -[(Ph)(Et 3 P) 2 Pt C≡C-R-C≡C Pt(PEt 3) 2 (Ph)] (R = 2,2'-Bipyridine-6,6'-diyl) have been synthesized by the reaction between [Eu(β-diketonate) 3 (H 2 O) 2 ] (β-diketone = btfa and nta) and Pt 2 bpy complexes in 1:1 M ratio in THF at room temperature. The complexes have been characterized by analytical and spectroscopic methods. The complexes are soluble in common organic solvents. The photophysical properties of the novel hetero-trinuclear complexes have been analyzed by steady-state and time-resolved emission spectroscopy. The complexes exhibit typical red emission of Eu(III). The absence of any residual ligand emission in the 400–550 nm region clearly attests the efficient energy transfer from the triplet state (T 1 = 20,408 cm−1) of Pt 2 bpy chromophore. The quantum efficiency (ϕ Eu) of [Eu(btfa) 3 Pt 2 -bpy] (Ф Eu ∼53.95%) is 1.88 times higher than [Eu(nta) 3 Pt 2 -bpy] (Ф Eu ∼28.63%), which could be due the larger value of the non-radiative decay rate (A nrad) ∼ 1754.41 s−1 for [Eu(nta) 3 Pt 2 -bpy] compared to A nrad ∼ 779.24 s−1 for [Eu(btfa) 3 Pt 2 -bpy]. Photometric characteristics of the complexes such as color correlated temperature (CCT) and luminous efficiency of the radiation (LER) suggest that the new materials may find potential application in high performance optoelectronic devices. Graphical abstract Image 1 Highlights • Two red emitting d-f-d complexes [Eu(btfa) 3 Pt 2 -bpy] and [Eu(nta) 3 Pt 2 -bpy] were synthesized. • [Eu(btfa) 3 Pt 2 -bpy] (Ф Eu ∼53.95%) is 1.88 folds higher than [Eu(nta) 3 Pt 2 -bpy] (Ф Eu ∼28.63%). • Extra C H resulted in larger A nrad ∼1754.41s−1 for [Eu(nta) 3 Pt 2 -bpy] to ∼779.24s−1 for [Eu(btfa) 3 Pt 2 -bpy]. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The charge injection/transport and phosphorescence of Pt(II) complexes are studied. • The dimeric structures and the weak intermolecular interaction are studied. • Square-planar complexes show unusual properties due to intermolecular interactions. Abstract A series of organoplatinum (II) complexes with different electron-donating substituents are designed and investigated using density functional theory (DFT) and time-dependent DFT approaches. By analyzing the ground and excited structures, absorption spectra, charge transport, and phosphorescence properties of five Pt(II) complexes, it is possible to forecast that [Pt(trpy)(C CAr′)]PF 6 (Ar′ = 2,6-Me 2 C 6 H 3) (complex 2c ·PF 6) could be an efficient phosphorescent material due to its better balanced electron/hole-transport performance. The emission transition of terpyridyl arylacetylide Pt(II) complexes is associated with 3MLCT/3LLCT transitions, while the emission transition of phenyl-bipyridine arylisocyanide Pt(II) complexes has 3MLCT/3LLCT/3IL character. To understand the structure-property relationships of the dimeric structures of Pt(II) complexes, we examined the regions and distribution of the different intermolecular non-covalent weak interactions by studying the dimers of pincer-type Pt(II) complexes. RDG analysis visualizes the regions of intermolecular Pt⋯Pt and π-π interactions in dimers. This work offers rich insight into the essential characteristics of Pt(II) aggregations and provides helpful information for designing the new and improved luminescent materials. [ABSTRACT FROM AUTHOR]

Abstract The reaction of electron rich [PtMe 2 (NN)] with SnMe 2 Cl 2 in a 1:3/Pt:Sn mole ratio resulted in formation of Pt(IV) complexes [PtMe 2 (SnMe 2 Cl)Cl(NN)] {NN = 4,4′-Me 2 bpy (4,4′-dimethyl-2,2′-bipyridine) (7); 5,5′-Me 2 bpy (5,5′-dimethyl-2,2′-bipyridine) (8); bphen (4,7-diphenyl-1,10-phenanthroline) (9)}. NMR data show that the resulting complexes exist as the sole product corresponding to that of trans oxidative addition of SnMe 2 Cl 2. The yellow polymorph of complex [PtCl 2 (5,5′-Me 2 bpy)] (10) was characterized by X-ray crystallography from the reaction of [PtMe 2 (5,5′-Me 2 bpy)] and excess of SnMe 2 Cl 2 due to the reductive elimination of 8. On the other hand, the reaction of [PtMe 2 (NN)] with SnEt 2 Cl 2 in a 1:3/Pt:Sn mole ratio resulted in formation of new complexes [PtMe 2 (SnEt 2 Cl)Cl(4,4′-Me 2 bpy)] (11), [PtMe 2 (SnEt 2 Cl)Cl(5,5′-Me 2 bpy)].SnEt 2 Cl 2 (12) and [PtMe 2 (SnEt 2 Cl)Cl(bu 2 bpy)].SnEt 2 Cl 2 (bu 2 bpy = 4,4′-di- tert -butyl-2,2′-dipyridine) (13). NMR data indicate that the Pt SnEt 2 Cl bond is weaker than the Pt SnMe 2 Cl bond. The X-ray crystal structure of 13 reveals that organoplatinum(IV) complex acts as a donor to the SnEt 2 Cl 2 to form an adduct in a distorted trigonal bipyramid with the axial Cl⋯Sn Cl and equatorial SnEt 2 Cl units. Moreover, the X-ray crystal structure of the new yellow form of [PtClMe(4,4′-Me 2 bpy)] (14), which has been formed by the crystallization of a mixture of [PtMe 2 (4,4′-Me 2 bpy)] and excess of SnEt 2 Cl 2 , is described. The reaction of dimethylplatinum(II) complexes with dimethyltin diisothiocanate are reported for the first time which occur via Sn-NCS bond cleavage to afford the organoplatinum(IV) complexes [PtMe 2 (SnMe 2 NCS)(SCN)(NN)] {NN = bpy (17); phen (18); 5,5′-Me 2 bpy (19); bu 2 bpy (20); bphen (21)}. The crystal structures of the novel thiocyanatoplatinum(IV) complexes [PtMe 2 (SCN) 2 (bpy)] (22) and [PtMe 2 (SCN) 2 (5,5′-Me 2 bpy)]. H 2 O (23) are discussed which have been obtained due to the α-elimination of SnMe 2. The crystal structures of 22 – 23 show that platinum adopts a slightly distorted octahedral geometry with trans - Pt(SCN) 2 configuration in which SCN is bonded through sulfur atom while the nitrogen atom is coordinated to tin. NMR data indicate that the products dissociate via α-elimination of SnMe 2 or reductive elimination of organotin(IV) compound and the stability of the organoplatinum(IV) compounds varies according to the trends [PtMe 2 (SnMe 2 Cl)Cl(NN)]>[PtMe 2 (SnMe 2 NCS)(SCN)(NN)]>[PtMe 2 (SnEt 2 Cl)Cl(NN)]. Graphical abstract Image 1 Highlights • Oxidative addition of [PtMe 2 (NN)] with SnR 2 X 2 (R = Me, Et; X = Cl, NCS) was studied. • Structure and reactivity are treated by IR, multinuclear and 2D-NMR spectroscopy. • Complexes [PtMe 2 (SnEt 2 Cl)Cl(NN)] show a tendency to adduct formation with SnEt 2 Cl 2. • Platinum(IV) complexes dissociate via α-SnMe 2 elimination or reductive elimination. • The X-ray crystal structure of the new six platinum and tin complexes are reported. [ABSTRACT FROM AUTHOR]

Abstract The new cyclometalated platinum(II) complexes [PtMe(CˆN)(pyrazine)] [CˆN = benzo[h]quinolate (bhq), 1a ; CˆN = 2-phenylpyridinate (ppy), 1c ] have been prepared by the reaction of corresponding dimethylsulfide complexes with pyrazine. These complexes contain two potential nucleophilic centers, Pt(II) center and free N atom of pyrazine which can compete in the reaction with methyl iodide to give Pt(IV) oxidative addition or N-methylation products, respectively. To investigate which center is more reactive toward MeI, DFT calculations (based on the free energy barrier needed for N-methylation versus oxidative addition reactions) and experimental evidence is considered to predict and explain site selectivity. Both experimental and theoretical studies show that the oxidative addition of MeI to cyclometalated Pt(II) complexes occurs readily to give the Pt(IV) complexes. Theoretical results support remarkably the kinetic results obtained through UV–Vis spectroscopy which suggest an S N 2 mechanism. Graphical abstract The new cyclometalated platinum(II) complexes [PtMe(CˆN)(pyrazine)] (CˆN = benzo[h]quinolate or 2-phenylpyridinate) contain two potential nucleophilic centers, Pt(II) center and free N atom of pyrazine which can compete in the reaction with methyl iodide. Image 1 Highlights • The preparation of new cyclometalated platinum complexes of the type [PtMe(C^N)(pz)], pz = pyrazine, was reported. • The competition between oxidative addition versus N-methylation in these platinum(II) complexes were theoretically studied. • The energy barrier for oxidative addition was less that for N-methylation. [ABSTRACT FROM AUTHOR]

Graphical abstract Two new platinum(IV) complexes containing 2,2′-dithiopyridine were synthesized. The obtained platinum(IV) complexes exhibited distorted octahedral geometry. The crystal structure of the arylplatinum(IV) complex has been determined by single crystal X-ray diffraction. The interaction of these complexes with calf thymus DNA was investigated. Highlights • Two new platinum(IV) complexes were synthesized. • The crystal structure of the arylplatinum(IV) complex has been determined. • The interaction of these complexes with calf thymus DNA was investigated. • The enthalpy and entropy of interaction of the complexes and DNA were calculated. • Fluorescence, UV–Vis and electrochemistry of the complexes were investigated. Abstract New platinum(IV) complexes containing N 2 S 2 donor atoms were synthesized by the reactions of [Pt(p -MeC 6 H 4) 2 (SMe 2) 2 ] and [PtCl 2 (DMSO) 2 ] with 2,2′-dithiopyridine (dtp) in 1:1 M ratio. In these reactions, 2-mercaptopyridine (mpy) ligands were formed through the cleavage of the disulfide bond in 2,2′-dithiopyridine. The mpy ligands were coordinated to the platinum center via the nitrogen and sulfur atoms and the obtained platinum(IV) complexes exhibited octahedral geometry. The complexes were characterized by FT-IR, 1H NMR, UV–Vis, elemental analyses and conductometry. The crystal structure of the arylplatinum(IV) complex containing C 2 N 2 S 2 donor atoms was determined by single crystal X-ray diffraction. The obtained molar conductance values revealed that the platinum(IV) complexes were nonelectrolytes. The interactions of the complexes with calf thymus DNA (CT-DNA) were investigated by absorption and fluorescence spectroscopy, cyclic voltammetry and viscometry methods. The intrinsic binding constants (K b) of the complexes with CT-DNA, obtained from UV–Vis absorption data, were 9.60 × 104 M−1 and 11.56 × 104 M−1. Furthermore, the enthalpy and entropy of the interaction between the platinum(IV) complexes and CT-DNA were calculated. The obtained data revealed positive enthalpy and entropy changes indicating a hydrophobic interaction between these complexes and CT-DNA. [ABSTRACT FROM AUTHOR]

Abstract To explore the utility of bis(dihydroxynaphthalene) ligands for the construction of supramolecular structures, we demonstrated the preparation of cage-shaped complexes by combining these ligands with hexacoordinate titanium(IV). The reaction of biphenylenebis(dihydroxynaphthalene) with TiO(acac) 2 proceeded in the presence of N -methylmorpholine in DMF and an M 2 L 3 -type cage was obtained by self-organization. As an extension of this work, the preparation of heterobimetallic molecular cages was examined by using combinations of titanium(IV), palladium(II) or platinum(II), and pyridyldihydroxynaphthalenes. Ti(IV)/Pd(II) cages were prepared in one pot by treatment of the pyridyldihydroxynaphthalene ligands with TiO(acac) 2 followed by PdCl 2 (MeCN) 2. In the preparation of Ti(IV)/Pt(II) cages, platinum(II)-bridged bis(dihydroxynaphthalene) ligands were isolated in advance from the reaction of pyridyldihydroxynaphthalene ligand precursors with K 2 PtCl 4 , which were then deprotected and reacted with TiO(acac) 2 in the same conditions as those for biphenylenebis(dihydroxynaphthalene). The precise structures of the Ti(IV)/Pd(II) and Ti(IV)/Pt(II) heterobimetallic cages were fully elucidated by X-ray crystallographic analysis. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

• Celebration of the 1000th volume of the journal of organometallic chemistry (" JOMC"). • Great thank you to all editors and members of the editorial board of JOMC from 1963 to the present time. • My (" Me ") most sincere appreciation to students, collaborators, staff, my employers, NWO, EU and industries. • Organo-copper and -lithium chemistry through selective self-assembly of organometallic and metal salt components. • Aspects of NCN-Pincer metal compounds; synthesis and coordination chemistry. To reach the 1000th Volume of the Journal of Organometallic Chemistry ("JOMC") is an incredible achievement, that deserves high respect and certainly represents a great service to the Organometallic Chemistry scientists. In a short review I discuss what triggered, late 1960s, my choice for Organometallic Chemistry, and the start of my long career in organometallic chemistry and homogeneous catalysis. Furthermore, the way that JOMC may have contributed to my research, is highlighted. Journals, such as JOMC, offer the possibility to disseminate one's scientific results to Society after a thorough check by anonymous reviewing by peers. This was one of my ("Me") first lessons learned. I was lucky enough to receive my training in a contract- and fundamental-research environment. In hindsight, organo-copper and -lithium chemistry, organozinc and (organo)(α -diimine)zinc radical chemistry and chemistry with the organometallic Pincer-metal platform were my favorite fundamental-research subjects. In a number of schemes, with concise legends, the development of these subjects with their highlights is presented. From the number of our papers in JOMC (about 125), is obvious that "We" felt free and truly at home with JOMC. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of unsymmetrical bidentate PNP'={(o -Tol) 2 P'N(R 1)P(R 2) 2 } and monophosphinoamine {(o -Tol) 2 P(R 1)NH} ligands presented. • Coordination of bidentate PNP' to Pt(II) as [Pt{κ2-(P,P')(PNP')}Cl 2 ] (3 N; N = A , C , D) complexes illustrated. • Cisplatin analogues cis -[Pt((o -Tol) 2 P(p -MePh)NH) 2 Cl 2 ] (2A) and trans -[Pt((o -Tol) 2 P(o -MePh)NH) 2 Cl 2 ] (2B) described. • Detailed 31P NMR spectroscopy study and five single crystal X-ray studies (2A , 2B , 3A , 3C , 3D) reported. • cis -[Pt((o -Tol) 2 P(p -MePh)NH) 2 Cl 2 ] (2A) and trans -[Pt((o -Tol) 2 P(o -MePh)NH) 2 Cl 2 ] (2B) evaluated for biological activity. An efficient and simple synthetic route to a new class of unsymmetrical diphosphinoamine {PNP'=(o -Tol) 2 P'N(R 1)P(R 2) 2 } and monophosphinoamine {(o -Tol) 2 P(R 1)NH} ligands are presented, which allowed the manipulation of the R 1 substituents on the amine as well as the cyclic R 2 substituents on the phosphorus atom. The unsymmetrical (o -Tol) 2 P'N(R 1)P(R 2) 2 ligands {R 1 = p -MePh (A), o -MePh (B), p -ClPh (C) or p -FPh (D)} and their coordination to a Pt(II) metal center as [Pt{κ2-(P,P')(PNP')}Cl 2 ] (3 N; N = A , C , D) type of complexes are presented. In addition, monophosphinoamine ligands {(o -Tol) 2 P(R 1)NH} are described, yielding the cisplatin analogue cis- [Pt((o -Tol) 2 P(p -MePh)NH) 2 Cl 2 ] (2A) , and trans- [Pt((o -Tol) 2 P(o -MePh)NH) 2 Cl 2 ] (2B). Five single crystal X-ray studies are reported (2A , 2B , 3A , 3C , 3D), together with a detailed 31P NMR spectroscopy study. The electrostatic and steric repulsions on the ortho -CH 3 on these types of ligands induces restricted rotation as seen by solution NMR spectra of all free ligands. The presence of two stable conformers (syn,syn,anti) and (syn,syn,syn) for the free PNP' ligands is illustrated, both in solution and solid state (31P MAS NMR). Moreover, in the synthesis, a scrambling/disproportionation of the unsymmetrical PNP' ligand is observed, yielding some 20% of the corresponding symmetrical PNP nucleophiles. However, the (syn,syn,anti)-conformer disappear upon coordination to the Pt(II), as required by the cis -[Pt(PNP')Cl 2 ] complexes. The two Pt-PN complexes cis- [Pt((o -Tol) 2 P(p -MePh)NH) 2 Cl 2 ] (2A) and trans- [Pt((o -Tol) 2 P(o -MePh)NH) 2 Cl 2 ] (2B) were evaluated for biological activity to ascertain whether the stereo chemistry on these would show more activity as analogous cisplatin and derivatives. Additionally, 2A and 2B were also screened for antimicrobial activity. Significant microbial inhibition against Gram-positive Staphylococcus aureus and two Fungi Cryptococcus neoformans and Candida albicans was found for complex trans -[Pt(p -MePh-PNH) 2 Cl 2 ] (2A), while the cytotoxicity evaluation of 2A against HEK293 human embryonic kidney cells displayed a moderate activity CC 50 of 18.1 μM. [ABSTRACT FROM AUTHOR]

• The crystal structures of several Pt(P(OR) 3) 2 X 2 were obtained and compared with spectral data. • Michaelis-Arbuzov-type dealkylation during synthesis was observed for some of the phosphite ligands. • Computational studies were used to understand the electronic structure of phosphite ligands. Air-stable phosphite-ligated platinum complexes of the form cis -Pt(P(OR) 3) 2 Cl 2 and cis -Pt(P(OR) 3) 2 Me 2 based on five small alkyl phosphite ligands have been synthesized and characterized. The crystal structures for several of these species are reported, allowing for comparison between spectroscopic and structural parameters. Michaelis-Arbuzov-type dealkylation during synthesis was observed for some of the phosphite ligands, and a dealkylated product was structurally characterized. Density Functional Theory (DFT) and Quantum Theory of Atoms in Molecules (QTAIM) was also used to examine the electronic structure of the phosphite compounds. The QTAIM results support the increased π-acidity of the phosphite ligands compared to analogous phosphines. Thermolysis experiments were performed to examine the stability and reactivity of Pt(P(OR) 3) 2 X 2 species. It was found that coordinated P(OiPr) 3 ligands decompose via cyclometallation and propylene extrusion. Air- stable phosphite-ligated platinum complexes of the form cis -Pt(P(OR) 3) 2 Cl 2 and cis -Pt(P(OR) 3) 2 Me 2 based on five small alkyl phosphite ligands have been synthesized and characterized. The crystal structures for several of these species are reported, allowing for comparison between spectroscopic and structural parameters. Michaelis-Arbuzov-type dealkylation during synthesis was observed for some of the phosphite ligands, and a dealkylated product was structurally characterized. Density Functional Theory (DFT) and Quantum Therory of Atoms in Molecules (QTAIM) was also used to examine the electronic structure of the phosphite compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Three bipyridine Pt(II) indoyl complexes have been synthesized. • The crystal structures of these bipyridine Pt(II) indoyl complexes have been determined. • The emission origin for these bipyridine Pt(II) indoyl complexes is assigned to come from the 3LLCT mixing with 3MLCT excited states. • These bipyridine Pt(II) indoyl complexes display mechanoluminescence. Three bipyridine platinum(II) complexes Pt-2-Pt-4 bearing indolyl ligand(s) have been synthesized through the hydroamidation of acetylide ligand(s) of Pt-1. The structures of Pt-1-Pt-4 were determined by single crystal X-ray diffraction. The photophysical properties of these structurally related complexes Pt-1-Pt-4 have been studied. Pt-1-Pt-4 in the solid state show emission peaks at 525–570 nm, which are assigned as the mixture of 3LLCT and 3MLCT excited states. Solids Pt-1-Pt-4 exhibit mechanoluminescence, and Pt-4G can be recovered back to solids Pt-4 upon adding a few drops of diethyl ether. This study provides a new way to synthesize bipyridine platinum(II) indolyl complexes using intramolecular hydroamidation of alkynyl moieties. [ABSTRACT FROM AUTHOR]

Two new square-planar Pt(II) complexes based on phenylacetylene ligand were prepared. Both complexes exhibit reversible mechanoluminescent property and can be used to develop rewritable data recording devices. [Display omitted] • Two Pt(II) complexes with reversible and reproducible mechanoluminescent property were prepared. • The luminescent response of two complexes to mechanical grinding exceeded 150 nm. • The mechanism of mechanoluminescent property is clearly revealed. • Both complexes have been successfully used to develop the rewritable data recording device. Two platinum(II) complexes, Pt(DiClBpy)(C CC 6 H 5) 2 (1) and Pt(DiBrBpy)(C CC 6 H 5) 2 (2) based on 4,4′-dichloro-2,2′-bipyridine (DiClbpy), 4,4′-dibromo-2,2′-bipyridine (DiBrbpy) and phenylacetylene ligands were synthesized and characterized. Both complexes display reversible and reproducible mechanochromic and mechanoluminescent properties with the luminescence red-shift exceeding 150 nm. Systematic studies on crystal structure, luminescence spectra, and PXRD demonstrate that the mechanochromic and mechanoluminescent properties of 1 and 2 are attributed to the formation/elimination of intermolecular Pt-Pt interactions during mechanical grinding/vapor absorption process, which lead to the transformation of the lowest energy excited states between MLCT and MMLCT transitions. In addition, based on such property, 1 and 2 were used as starting functional material to successfully develop the rewritable data recording device. [ABSTRACT FROM AUTHOR]

[Display omitted] • Five Pt(II) complexes with different alkyl are designed and synthesized. • The photophysical properties of complexes in solution are essentially the same. • Five complexes have different AIPE activities in the aggregated state. • The introduction of different alkyl groups changes the AIPE activity of complexes. Different alkyl chains were introduced into alkynyl-naphthalimide ligands and bipyridine ligands to synthesize five platinum complexes, their structures were characterized and the photophysical properties were systematically investigated. It was found that the introduction of alkyl chains had no obvious effect on the absorption and emission of these complexes in dilute solution, while influence aggregation-induced emission activity in aggregated state. In the mixed solvent system of tetrahydrofuran and ethylene glycol, the shorter alkyl chains on the bipyridine ligands strengthen the aggregation-induced phosphorescence emission (AIPE) properties of complexes, however, the introduction of different alkyl chains on the alkynyl-naphthalimide ligands makes no difference on their AIPE properties. Combining the single crystal results and Hirshfled surface analysis, the photophysical properties of these complexes in aggregated state were affected by the stacking modes, which is due to the different interactions. This research may broaden the scope for the design of multi-functional materials adopting different aggregation states. [ABSTRACT FROM AUTHOR]

• Trans-spanning diphosphine ligands P((CH 2) 14) 3 P create cage like environments. • Within such coordination cages sufficiently small ligand sets ML y can rotate. • Tetrachloro and tetrabromo platinum(IV) adducts thereof have been synthesized. • A tetramethyl platinum(IV) adduct has been isolated in both cis and trans forms. • Analogs of such species with dipolar rotators are candidates for molecular gyroscopes. Reactions of the platinum(II) dihalide complexes t r a n s - Pt (X) 2 (P ((C H 2) 14) 3 P) (X = Cl , t r a n s - 4 ; B r , t r a n s - 6) and excess X 2 give the platinum(IV) tetrahalide complexes t r a n s - Pt (X) 4 (P ((C H 2) 14) 3 P) (t r a n s - 5 , t r a n s - 7) in 84-95% yields. Their crystal structures are determined and the PtX n conformations and bond lengths compared to those of trans - 4 and trans - 6. In one instance, a reaction of trans - 6 and MeMgBr (2.4 equiv) gave not the precedented product c i s - Pt (Me) 2 (P ((C H 2) 14) 3 P) , but rather a small amount of the platinum(IV) tetramethyl complex t r a n s - Pt (Me) 4 (P ((C H 2) 14) 3 P) (trans - 8), as verified crystallographically and by diagnostic NMR signals. Independent syntheses were attempted. Reactions of trans - 5 or trans - 7 with excesses of common sources of Me– were unsuccessful. Thus, the free dibridgehead diphosphine P((CH 2) 14) 3 P, which can incorporate PtX 2 to give trans - 4 or trans - 6 , was treated with the PtMe 4 source Pt 2 Me 8 (µ -SMe 2) 2. However, this gave instead the isomeric species cis - 8 , and attempts to establish cis / trans equilibria were unsuccessful. A new "solar system" of octahedral platinum(IV) complexes has been discovered. These feature novel trans or cis dibridgehead diphosphine ligands and tetrabromo, tetrachloro, or tetramethyl ligand sets. The increasing orbit diameters depicted may mirror the rotational lifetimes or barriers in solution. [Display omitted] [ABSTRACT FROM AUTHOR]

Three new square-planar platinum(II) complexes, Pt(PhC≡CbpyC≡CPh)(C≡CC 6 H 4 -X-2) 2 [PhC≡CbpyC≡CPh = 4,4′-bis(2-phenylethynyl)-2,2′-bipyridine; X = F(1), Cl(2), and Br(3)] were synthesized and characterized. Upon exposure of the ground sample to volatile organic compound (VOC) vapors, a series of metastable structures of three complexes, including yellow solvent-free species 2 and 3 , orange species 1 , 2 ·ClCH 2 CH 2 Cl and 3 ·ClCH 2 CH 2 Cl, red species 1· 1.5(CHCl 3), 2 ·½(CH 2 Cl 2), 2 ·½(ClCH 2 CH 2 Cl), 3· ½(Toluene), and 3 ·½(ClCH 2 CH 2 Cl) were isolated. All three complexes exhibit vapor-, thermo-, and mechanical-grinding-triggered triple-stimuli-responsive luminescent switching properties. More interestingly, upon exposure to ClCH 2 CH 2 Cl vapor, the red species 2 ·½(CH 2 Cl 2) or 3· ½(Toluene) undergo an unusual time-dependent two-stepwise luminescent switching process and convert to the orange species 2 ·ClCH 2 CH 2 Cl or 3 ·ClCH 2 CH 2 Cl via intermediate 2 ·½(ClCH 2 CH 2 Cl) or 3 ·½(ClCH 2 CH 2 Cl). Furthermore, 1· 1.5(CHCl 3) also displays a two-stepwise thermoluminescent property and is transformed into orange species 1 via intermediate 1· ⅛(CHCl 3). Furthermore, both 2 and 3 present the irreversible vapochromic and vapoluminescent properties as the yellow and orange species could not be converted to each other or transformed to the red species by absorbing the corresponding VOC vapors. Systematic studies revealed that the vapor-, thermo-, and mechanical-grinding-triggered triple-stimuli-responsive luminescence switching properties of 1 – 3 are due to the structural conversion and resultant changes of the lowest-energy excited states. The crystal structure, 1H NMR, luminescence spectra and PXRD measurements demonstrate that the two-stepwise luminescent switching behavior of complexes are associated with the stacking structure of species with same kind and different amount of solvent molecule. The irreversible vapoluminescent property of 2 and 3 are most likely due to the closed stacking of species which prevent the inserting of solvent molecules into the crystal lattice. In addition, complexes 1 – 3 have good application prospects in the visual identification of CHCl 3 , CH 3 CN and 1,2-dichloroethane vapors. [Display omitted] • Three new vapor-, thermo- and mechanical grinding triggered triple-stimuli-responsive platinum(II) complexes were prepared. • Complex 2 and 3 exhibit irreversible vapochromic and vapoluminescent properties. • 2· ½(CH 2 Cl 2) and 3· ½(Toluene) display the time-dependent two-stepwise vapoluminescent property. • 1· 1.5(CHCl 3) also presents a two-stepwise thermoluminescent property. • The mechanism of luminescent switching properties are clearly revealed. [ABSTRACT FROM AUTHOR]

Borylation of arenes with bis(pinacolato)diboron catalyzed by sterically encumbered NHC platinum complexes proceeds predominantly at ortho -position even in the absence of a directing group (o : m : p ratio up to 10: 3: 1). The similar borylation with pinacolborane would proceed less selectively. [ABSTRACT FROM AUTHOR]

Herein, we present a flash nanoprecipitation process for one-step formation of soft colloidal particles, in which platinum (II) acetylacetonate is entrapped within poly(styrene-co-acrylonitrile) nanospheres. The protection of the polymer matrix in the flash nanoprecipitated composites would ensure that the monodisperse platinum nanoparticles are uniformly dispersed in the carbon matrix after carbonization. Electrochemical characterization shows that the obtained Pt-carbon nanocomposites (denoted as Pt@NC) exhibit a high catalytic performance and low polarization loss toward oxygen reduction reaction (ORR) in an alkaline electrolyte via a favorable four-electron pathway. [ABSTRACT FROM AUTHOR]

A solvent-specific reduction of Pt IV iodo complexes into Pt II by iodide ions was found: in acetone, Pt IV iodo complexes are almost quantitatively reduced into Pt II , and iodine, which is formed upon the reduction, is bound in a poorly soluble polymeric complex with NaI and acetone. The revealed solvent-specific reduction of Pt IV into Pt II was used for sequential alkylation of Pt II iodo complexes with iodoacetone to form mono-, bis-, and tris-acetonyl Pt IV derivatives and also with iodoacetic acid to give mono- and bis-carboxymethyl Pt IV complexes. The reaction of iodoacetic acid is accompanied by its catalytic reduction into acetic acid. The organic ligands in the formed organoplatinum compounds are mutually cis , which is essential for further accomplishment of C-C coupling reactions. [ABSTRACT FROM AUTHOR]

The post-assembly modification provides a powerful strategy for constructing functional polymeric materials by the selection of suitable functional groups or external stimuli. Herein, we took advantage of photodimerization of coumarins to link the pendent coumarin functional groups of hexagonal metallacycles 1 and 2 to give metallacycle-cored supramolecular polymers 1 p and 2 p under UV irradiation at 365 nm. [ABSTRACT FROM AUTHOR]

Background: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.Findings: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).Interpretation: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.Funding: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma.Methods: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up.Findings: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes.Interpretation: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents.Funding: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities. [ABSTRACT FROM AUTHOR]

As a third-generation platinum drug, oxaliplatin has been widely applied in colorectal cancer (CRC); however, acquired resistance to oxaliplatin has become a major obstacle. In the present study, we found that the nuclear transcription factor Y subunit beta (NFYB) and E2F transcription factor 1 (E2F1) expression levels were significantly higher in oxaliplatin-resistant DLD1 and RKO CRC (OR-CRC) cells than in non-resistant cells. Additionally, highly expressed NFYB transactivated the E2F1 gene, which is important to maintain oxaliplatin resistance in OR-CRC cells. And Sirt1-dependent deacetylation suppresses the proapoptotic activity of E2F1 in OR-CRC cells. Through profiling the transcriptome of OR-CRC cells following E2F1 knockdown, CHK1 was identified as a target of E2F1. Deprivation of CHK1 sensitized OR-CRC cells to oxaliplatin. In vitro and in vivo phenotype experiments confirmed that an intact NFYB-E2F1-CHK1 axis was required to suppress oxaliplatin-induced apoptosis and maintain the tumorigenicity in OR-CRC cells. Knockdown of E2F1 in OR-CRC cells also decreased the expression of Pol κ, which was essential for CHK1 activation. Consistently, a high level of NFYB, E2F1, or CHK1 predicted poor survival in CRC patients, especially with oxaliplatin treatment. Collectively, the NFYB-E2F1 pathway displays a crucial role in the chemoresistance of OR-CRC by inducing the expression and activation of CHK1, providing a possible therapeutic target for oxaliplatin resistance in CRC. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin-based chemotherapy is an alternative systemic treatment for patients with metastatic hepatocellular carcinoma (HCC) who were refractory or intolerant to sorafenib. To date, there have been no biomarkers reported to monitor the therapeutic efficacy and to predict the outcomes of HCC patients receiving oxaliplatin-based chemotherapy.Methods: Eighty-one HCC patients with elevated baseline α-fetoprotein (AFP) levels and extrahepatic spreading who received oxaliplatin-based chemotherapy between 2012 and 2014 were retrospectively enrolled in this study. Two AFP tests were performed, at baseline and 2-4 weeks after the initiation of chemotherapy. The change in AFP levels was calculated for survival analysis.Results: In the AFP decline group (decreased compared to baseline), the median progression-free survival (PFS) and overall survival (OS) were 7.0 months and 12.3 months, respectively. In the AFP nondecline group, the median PFS and OS were 2.3 months and 3.0 months, respectively. The difference in OS between the two groups was significant (p < 0.005). In the multivariate analysis for disease progression, the best response to chemotherapy and AFP decline were independent factors, with p values of 0.004 and 0.009, respectively. In the multivariate analysis for OS, the baseline Child-Pugh score, best response to chemotherapy, and AFP decline were independent prognostic factors, with p values of 0.01, 0.001, and 0.008, respectively. Additionally, the unit change in AFP level was predictive of PFS and OS with p values of 0.007 and 0.001, respectively.Conclusion: The change in AFP levels 2-4 weeks after initiating oxaliplatin-based chemotherapy is useful to predict treatment response and survival. [ABSTRACT FROM AUTHOR]

Background: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients.Methods: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing.Findings: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis).Interpretation: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.Funding: Merck KGaA, and Pfizer Inc. [ABSTRACT FROM AUTHOR]