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Background: The addition of trastuzumab (H) to pre-operative chemotherapy in HER2+ breast cancer (H+BC) increases the rate of pathological complete response (pCR). TCH is a widely used adjuvant regimen in early stage H+BC. Lapatinib (L) is a small molecule HER2 antagonist that produces responses following H failure, and has been reported to augment H activity in combination in vitro. We compared neo-adjuvant docetaxel, carboplatin (TC) + H v TCL v TCHL in pts with H+BC. Methods: Pts with stages Ic–III H+BC were randomized to receive neo-adjuvant TCH, TCL or TCHL (ICORG/CTRIAL-IE 10-05, NCT01485926 www.clinicaltrials.gov). Pts subsequently underwent surgery and received H post-operatively for 1 year from the first dose of H. The primary endpoint of the trial was pCR. Secondary objectives were overall survival (OS) and relapse-free survival (RFS) and molecular and pharmacological markers of response. This study was supported by GSK, Novartis, The Cancer Clinical Research Trust and The Caroline Foundation. Results: When the NCIC CTG MA.31 trial reported inferior outcomes for L compared to H, we discontinued the TCL arm. This abstract reports data on the 76 pts recruited to the TCH and TCHL arms only, who included stage II (69.7%; n=53) or stage III disease (21.1%; n=16, with stage unknown for 9.2% (n=7). The final analysis set numbered 75 pts. Clinicopathological characteristics were well balanced between arms. The pCR rate of the two arms TCHL and TCH were virtually identical at 51.6% and 52.8% respectively (Fisher’s test p-value: 1.000). TCHL pts had significantly superior 5 year relapse-free survival (relative risk (RR) 0.171, 95% CI 0.041 – 0.713; log-rank test p-value = 0.009). OS was comparable between the TCH and TCHL groups (RR 0.205, 95% CI 0.025 – 1.675); log-rank test p-value = 0.2). Median RFS and OS were not reached. The most frequent serious adverse event was diarrhoea which occurred in 21.3% (n=16/75) pts (Grade 3 diarrhoea 13/16). One pt (TCH arm) who did not have protocol-mandated prophylactic G-CSF had a Grade 5 toxicity. One TCHL pt had a self-limiting diverticular perforation. There was a significantly higher frequency of severe diarrhoea in pts who received the TCHL regimen (Grade 3+, 32.4% vs 10.5%, p=0.038). The use of prophylactic loperamide reduced the frequency of diarrhoea in both the TCHL arm (86.2% vs 44.4%, p=0.004) and in the TCH arm (58.8% vs 24%, p=0.009). A post lock audit with minimum 9-year follow-up showed relapse rates of 15% TCHL vs 33% TCH. Conclusions: The study did not meet its primary pCR endpoint possibly due to a high TCH pCR rate, and small numbers. TCHL produced a statistically significant improvement in RFS compared to TCH. TCHL produced a higher rate of gastro-intestinal toxicity, but the use of loperamide significantly reduced the frequency of diarrhoea. These data suggest that anti-HER2 TKIs merit further investigation in the neo-adjuvant treatment of early stage H+BC. Table 1. pCR rates, 5 year RFS and OS results for ICORG/CTRIAL-IE 10-05 (NCT01485926) study pts. * significant, p Citation Format: John Crown, Denis M. Collins, Alex J. Eustace, Maccon Keane, Linda Coate, John Kennedy, Seamus O’Reilly, Catherine Kelly, Miriam O’Connor, Michael J. Martin, Conleth Murphy, Karen Duffy, Janice Walshe, Thamir Mahgoub, Giuseppe Gullo, Brian Moulton, Alberto Alvarez-Iglesias, Imelda Parker, Bryan Hennessy. Five year follow up of a randomized phase II comparison of neo-adjuvant docetaxel, carboplatin, trastuzumab with or without lapatinib in HER-2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-09.

Purpose: Cell-free DNA (cfDNA) analysis in plasma is an emerging technique with numerous applications in oncology. We employed cfDNA to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients and to predict outcome to bevacizumab (BVZ) combination therapy. Experimental Design: Low coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples from 74 mCRC patients participating in the CTRIAL-IE 12-16 AC-ANGIOPREDICT Phase II clinical trial (NCT01822444), prior to receiving BVZ, and analyzed for CIN (3 subclusters with low, intermediate and high CIN, respectively) and nucleosomes. For 61/74 mCRC patients, plasma samples before and after BVZ treatment were available and used for targeted methylation sequencing. A validation cohort of mCRC plasma samples (n= 24) from the University Medical Center Mannheim (UMM) was similarly profiled. Results: Based on cfDNA CIN profiles, we subtyped mCRC patients with 92.3% accuracy of sample distinction into low and high CIN clusters (cluster 1 against cluster 2 and 3), demonstrating concordance between matched plasma and tumor samples. Improved survival outcome was observed in CIN high patients. Plasma-based CIN clustering and improved survival for CIN high patients was also confirmed in the UMM cohort. NF and methylation profiles differed between CIN clusters and healthy individuals, and could reliably separate cluster 1 from cluster 2 and 3 samples (AUC=0.72 and 0.85 respectively). A large methylation score decrease after BVZ treatment was associated with improved overall survival (p = 0.013). Conclusions: cfDNA can be analyzed to predict outcome to BVZ in mCRC patients. Detection of CNAs, NFs and methylation profiles facilitated stratification of samples into CIN clusters and informed patient response to treatment. Citation Format: Ian S. Miller, Valentina Thomas, Tom Venken, Ingrid Arijs, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P. Ebert, Jochen Prehn, Rut Klinger, Darran P. O’Connor, Brian Brian Moulton, Verena Murphy, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Nicole Prannikar, Judith Franz-Werner, Hans-Peter Feustel, Diether Lambrechts, Annette T. Byrne. Analysis of cell free DNA to predict outcome to Bevacizumab combination therapy in metastatic colorectal cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5584.

Background: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. Methods: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). Results: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1–72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12–54) months in TN patients versus 38 (22–71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. Conclusions: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. Trial Registration ClinicalTrials.gov Identifier: NCT00911716.

Background: The addition of H to chemotherapy improved disease outcome in HER2+ MBC. The combination of H and L with chemotherapy improved event free survival (EFS) in the neo-adjuvant setting but not in the adjuvant setting. However, improved EFS did not translate to overall survival benefit. This international trial (ICORG (CTRIAL-IE) 11-10/NCT01526369) compared the efficacy of TH vs. THL in first line treatment of HER2+ MBC. The primary aim of this study was to assess any benefit for the addition of L to TH in an advanced HER2+ breast cancer patient population. Target accrual was not met due to changes to standard of care mid-study. Methods: Patients (Pts) (n= 75 enrolled, randomized 1:1) received weekly T (80mg/m², for 3 weeks of a 4 week cycle) + H (8mg/kg loading dose on cycle 1 day 1 and 4mg/kg every 2 weeks) + L (1,000 mg daily)) until disease progression, unacceptable toxicity or consent withdrawal. The primary outcome measure was progression free survival (PFS). Secondary outcome measure was overall survival (OS). Eligibility criteria included: Female > 18 years, invasive MBC, measurable disease by RECIST criteria V1.1, HER2+ by testing of the primary tumour and if available the biopsied metastatic lesion. No prior systemic therapy for metastatic disease (except one line of hormonal therapy for metastatic disease without H). No recurrence within 12 months (mo) from completion of adjuvant chemotherapy to the development of metastatic disease. No recurrence within 6 mo from completion of adjuvant H to the development of metastatic disease and no prior L treatment. Results: Of the 75 pts enrolled, n=65 (TH n=34, THL n=31) were included in the PFS analysis. Median PFS (95% CI) was numerically higher, but not statistically significant, in THL (24.0 mo (9.5, 34.5)) vs TH (19.3 mo (8.7, 22.7)), HR 0.827, p= 0.601. For OS analysis, n=69 (TH n=35 and THL n=34) were included. 41/69 (59.4%) had no prior therapy. No statistically significant, clinically meaningful improvement in OS (Median (95% CI)) was observed (TH 53.8 mo (41.8, -) vs. THL 45.6 mo (29.7, -), HR 1.048, p=0.891). Analysis of the safety set (n=70 (TH n= 36, THL n=34)) revealed a higher incidence of Grade 3/4 AEs in THL (61.8%) vs. TH (50%), p=0.322. There were 2 on-treatment fatalities due to adverse events (AEs) in the THL arm, one due to respiratory failure, the other due to central nervous system metastasis. There were no on-treatment fatalities in the TH arm. GI disorders were the most prevalent AE, with the incidence of diarrhea significantly higher in the THL arm (88% vs. 42%, p Citation Format: John Crown, William Jacot, Denis M. Collins, Linda Coate, Anna Saetersdal, M John Kennedy, Catherine Kelly, Blanca Cantos Sanchez De Ibarguen, Raquel Andrés Conejero, Luis Costa, Margarida Brito, Maccon Keane, Pedro Sanchez Rovira, Miguel Martin, Miriam O'Connor, Manuel Ramos Vazquez, Elena Alvarez, Seamus O'Reilly, Johanna Mattson, Laura Jolis Lopez, Alvaro Rodriguez Lescure, Esperanza Blanco, Coralia Bueno Muino, Brian Moulton, Norma O'Donovan, Andres Hernando, Marc Nolan, Imelda Parker, Giuseppe Gullo, Bryan Hennessy. A phase III randomized study of paclitaxel (T) and trastuzumab (H) versus T, H and lapatinib (L) in first line treatment of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT212.

Background The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies. Methods Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry. Results PIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05). Conclusions Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours. Trial registration ClinicalTrials.gov, NCT01485926. Registered on 2 December 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0883-9) contains supplementary material, which is available to authorized users.

Three new tetranuclear complexes [MnIII2CoIII2O2(L)2][ClO4]2 (1), [MnIII2FeIII2O2(L)2][ClO4]2 (2), and [MnIII2MnIII2O2(L)2][MnII(NCS)4] (3) have been synthesized through reactions of the mononuclear [MnIIIL] precursor with the corresponding metal perchlorate under aerobic conditions [H3L = tris(2-salicylaldimine)amine, a condensation product between tris(2-aminoethyl)amine and salicylaldehyde in a 1:3 molar ratio]. These compounds have been characterized by spectroscopic and analytical techniques including single-crystal X-ray structure analysis, electron paramagnetic resonance (EPR) spectroscopy, Mossbauer spectroscopy, and magnetic measurements. The structure of 1 consists of oxo-/phenoxo-bridged CoIII and MnIII centers in a defective double-cubane topology. The molecules of 2 and 3 have similar structures with the CoIII centers changed to FeIII centers in 2 and to MnIII centers in 3. These isostructural complexes have been scrutinized with regard to changes in distortions (distances and angles) of the metal coordination spheres. Magnetic studies indicate that 1, 2, and 3 show predominant antiferromagnetic interactions. Changes in the electronic properties concomitant with changes in the distortions in 1, 2, and 3 are analyzed in terms of magnetostructural correlations.

Background: The addition of trastuzumab (H) to pre-operative chemotherapy in H+BC increases the rate of pathological complete remission (pCR). H causes cardiac toxicity, especially when given with anthracyclines (Anth). TCH is a widely used adjuvant regimen with decreased cardiac toxiciy. We reported that TCH produces pCR in 40% of non-randomised pts with H+BC. Lapatinib is an alternative HER2 antagonist, which produces responses following trastuzumab failure, and which has been reported to augment H activity in combination. We studied the non-Anth regimens TCH v TCL v TCHL in pts with H+BC. The primary objective of this study was pCR. Secondary endpoints were toxicity and translational. Methods: Eligibility criteria included: primary BC, HER-2 +, node + disease (histologically or cytologically confirmed) or node-negative with >T1, normal left ventricle ejection fraction, no active/uncontrolled cardiovascular disease, normal organ and marrow function. Treatment consisted of 6 cycles of D (75mg/m2) + C (AUC 6) q3 weekly and H (8 mg/kg on cycle 1 day 1 and 6 mg/kg q3weekly thereafter for one year) ± L (1000mg OD) for up to 1 week before surgery. A sample size of 36 evaluable pts is required to detect an absolute 25% difference in the pCR rate between the hypothesised 65% pCR rate vs the historical-control pCR rate of 40%. Results: Following presentation of NCIC MA31 we decided to suspend accrual on our TCL arm.78 female pts were accrued to TCH/TCHL in 11 ICORG sites between 12/2010- 06/2013. Of 40 patients accrued to TCHL, only 18 pts completed 6 cycles. 17pts came off study early due to toxicity, 3 pts after cycle 3, 2 pts after cycle 2, 12pts after cycle 1. (1 patient was also registered but never started). Of 38 pts accrued to the TCH arm,33 pts completed 6 cycles,2 pts completed 5 cycles and 2 pts w/d after cycle 1. 3 TCHL & 1 TCH pt still remain on Rx. 2 pts have not yet had surgery. 52 SAEs occurred on study, 49 involving hospital admission, & 3 of medical significance. The most frequent SAEs were diarrhoea (10), febrile neutropenia (4), nausea (4), neutropenic sepsis (3), dehydration (2), wound infection (2), vomiting (2) neutropenia (2) decreased haemoglobin (2), GI perforation (1). There was 1 fatality on the TCH arm due to Neutropenic sepsis and typhlitis. One TCHL pt suffered GI perforation at cycle 1. pCR rates were 48% (16/33) for the TCH arm and 44% (7/16) for the TCHL arm. Translational studies are underway. Conclusions: TCH containing treatment produces a high rate of pCR. TCHL will not produce a statistically higher rate of pCR in this sample. The addition of lapatinib to TCH results in substantial GI toxicity. TCHL appears to be less tolerable than other active chemotherapy +H+L regimens such as that used in Neo-ALLTO. ICORG is currently leading an international study of paclitaxel+H +/- L in metastatic BC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-25.

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grou...

The December 2011 release of a draft United States Food and Drug Administration (FDA) guidance concerning regulatory classification of pharmaceutical cocrystals of active pharmaceutical ingredients (APIs) addressed two matters of topical interest to the crystal engineering and pharmaceutical science communities: (1) a proposed definition of cocrystals; (2) a proposed classification of pharmaceutical cocrystals as dissociable “API-excipient” molecular complexes. The Indo–U.S. Bilateral Meeting sponsored by the Indo–U.S. Science and Technology Forum titled The Evolving Role of Solid State Chemistry in Pharmaceutical Science was held in Manesar near Delhi, India, from February 2–4, 2012. A session of the meeting was devoted to discussion of the FDA guidance draft. The debate generated strong consensus on the need to define cocrystals more broadly and to classify them like salts. It was also concluded that the diversity of API crystal forms makes it difficult to classify solid forms into three categories that...

During milling, components are subjected to shear and tensile stresses, which can result in physical phase transformations. The purpose of the work described in this report is to understand the pathway by which two test compounds, d -salicin and γ-indomethacin, undergo a crystalline to amorphous transformation during cryomilling. The results show that the transformation cannot be described by a standard one-phase or two-phase disordering mechanism. In the one-phase model, a continuous set of states exist, linking perfect crystalline with completely amorphous material, whereas the two-phase model of disorder depicts the material as a binary mixture of crystalline and amorphous fractions. Instead, a model is proposed where two one-phase regions, defected crystalline and amorphous regions, are separated by a distinct transition.

Postsynthetic strategy based on organic coupling reactions has been explored for the synthesis of novel coordination complexes with larger dimensions. A discrete coordination species with a paddlewheel motif, dicopper(II) tetracarboxylate Cu2(OOC-C6H4-N3)4(quinoline)2 (SBU1), was covalently modified with methyl propiolate via “Click” reaction to generate a new coordination compound Cu2(OOC-C6H4-C2N3H-COOCH3)4·(quinoline)2 (1). The combination of single-crystal X-ray diffraction, diffusion NMR and ESR has confirmed the success of covalently modifying SBU1 and the retention of the structural integrity after the postsynthetic modification.

A homologous series of neutral Zn(II) coordination complexes including Zn(PNO)2 (1), Zn(PNO)2(3-Br-Py) (2), [Zn(PNO)2(1,10-phenanthroline)](H2O)5/3 (3), and Zn(PNO)2(2,2′-Bipy) (4), where PNO = dep...

Six novel metal–organic complex assemblies constructed from a conformation-flexible ligand – pyridine-4-acetamide (PAT) and inorganic CuII and CoII salts have been synthesized and structurally characterized by single crystal X-ray diffraction analysis. Crystal structure analysis reveals five types of architectures by variation of metal salts. In {[Cu(PAT)2Cl2]}n (1) and {[Co(PAT)2Cl2]}n (3), PAT ligands bridge metal centers to form one-dimensional chains. The chains are extended to three dimensions with the aid of two types of hydrogen bonded motifs ( R 4 2 ( 8 ) ) and R 2 2 (12)). {[Cu(PAT)2(NO3)](NO3)(THF)}n (5) which exhibits two-dimensional coordinating layers forms open channels filled with solvent molecules. In [Cu(PAT)2Cl2] (2), [Co(PAT)2Cl2] (4) and [Co(PAT)4(H2O)2](NO3)2(THF)2 (6), PAT is observed as a monofunctional ligand. Complex 2 forms one-dimensional hydrogen bonded chains. Crystal structure of complex 4 has a two-dimensional infinite hydrogen-bonded network with R 4 2 ( 8 ) and R 2 2 ( 8 ) motifs formed by complementary amide–amide hydrogen bonds. [Co(PAT)4(H2O)2](NO3)2(THF)2 (6) crystallizes in centrosymmetric I41/a space group. Complex 6 forms chiral channels which are filled with twisted solvent helices and anion helices. Within each channel the solvent helix and the anion helix have the same handedness; and adjacent channels have opposite handedness. Complexes 1, 2 and complexes 3, 4 illustrate examples of conformational supramolecular isomerism in {[Cu(PAT)2Cl2]}∞ and {[Co(PAT)2Cl2]}∞, respectively. In these complexes, changes of PAT conformations and coordination geometry of metal center induced the structural versatility.

The active pharmaceutical ingredient 5-chloro-8-hydroxyquinoline, which has shown potential antituberculosis activities, crystallizes in two different polymorphic forms, denoted Form I (Banerjee et al. Acta Crystallogr, Sect C: Cryst Struct Commun C42:1408–11, 1986) and Form II. In this present work, we have succeeded in crystallization of Form II. The cell dimensions of the monoclinic P2(1)/c Form II are a = 13.132(3) A, b = 3.7632(8) A, c = 15.459(3) A and β = 99.69(3)°. Characterizations for Form II have been conducted in details. Finally the solubilities and dissolution kinetics of both polymorphs have been measured in various media at different temperature. The measurement results highlight the fact that Form II has higher water solubility and faster dissolution rate than Form I. 5-chloro-8-hydroxyquinoline has been well known for its antifungal, antibacterial and antiamebic activities for decades. Recently, 5-chloro-8-hydroxyquinoline was reported to exhibit good antituberculosis activity even for multidrug-resistant isolates as well. The first crystalline form (Form I) of 5-chloro-8-hydroxyquinoline was reported in 1986 by Banerjee and Saha. Then there has been no new crystalline form of 5-chloro-8-hydroxyquinoline discovered from then on. In this work, we primarily reported the crystal structure of a novel polymorph (Form II) of 5-chloro-8-hydroxyquinoline. Solubility and dissolution kinetic measurements of both polymorphs were performed as well.

Reaction of hexaazamacrocycle, 1,4,7,10,13,16-hexaazacyclooctadecane (L = [18]aneN6) with boron trifluoride etherate in an aqueous solution of hydrofluoric acid yields the proton-transfer complex of the composition [H6L(F) (BF4)5] · 3H2O (1). X-ray crystallographic analysis shows that the macrocyclic cation adopts an unusual conformation to accommodate the fluoride anion and to keep the tetrafluoroborate anions in a close proximity. The tetrafluoroborate anions and water molecules participate in NH⋯F, NH⋯O and OH⋯F hydrogen bonding responsible for the 3D supramolecular architecture.

The employment of the anion of 2,6-diacetylpyridine dioxime (dapdoH2) as a pentadentate chelate in transition metal cluster chemistry is reported. The syntheses, crystal structures, and magnetochemical characterization are described for [Mn6O2(OMe)2(dapdo)2(dapdoH)4](ClO4)2 (1), [Mn6O2(OMe)2(dapdo)2(dapdoH)4][Ca(NO3)4] (2), and [Mn8O4(OH)4(OMe)2(N3)2(dapdo)2(dapdoH)2(H2O)2] (3). The reaction of [Mn3O(O2CMe)6(py)3](ClO4) with 3 equiv of dapdoH2 (with or without 2 equiv of NEt3) in MeOH gave 1. The same cation, but with a [Ca(NO3)4]2- anion, was found in complex 2, which was obtained from the reaction in MeOH between Mn(NO3)2, Ca(NO3)2, and dapdoH2 in the presence of NEt3. In contrast, addition of NaN3 to several reactions comprising MnCl2, dapdoH2, and NEt3 in MeOH gave the octanuclear complex 3. Complexes 1-3 all possess rare topologies and are mixed-valence: 2MnII, 4MnIII for 1 and 2, and 2MnII, 6MnIII for 3. The core of the cation of 1 and 2 consists of two edge-sharing Mn4 tetrahedra at the center of each of which is a micro4-O2- ion. Peripheral ligation is provided by two micro-OMe-, four micro-dapdoH-, and two micro3-dapdo2- groups. The core of 3 consists of two [MnIIMnIII3(micro3-O)2]7+ "butterfly" units linked together by one of the micro3-O2- ions, which thus becomes micro4. Peripheral ligation is provided by four micro-OMe-, two micro-OH-, two micro-dapdoH-, and two micro4-dapdo2- groups. Variable-temperature, solid-state dc and ac magnetization studies were carried out on complexes 1-3 in the 5.0-300 K range; the data for 1 and 2 are identical. Fitting of the obtained magnetization versus field (H) and temperature (T) data by matrix diagonalization and including only axial anisotropy (zero-field splitting, D) established that 1 possesses an S=5 ground state with D=-0.24 cm(-1). For 3, low-lying excited states precluded obtaining a good fit from the magnetization data, and the ground state was instead determined from the ac data, which indicated an S=1 ground state for 3. The combined work demonstrates the ligating flexibility of pyridyl-dioxime chelates and their usefulness in the synthesis of new polynuclear Mnx clusters without requiring the co-presence of carboxylate ligands.

Three new crystalline coordination polymers [Mn3(TDC)4(H2O)4](2,6-lutidine)2(H2O)3 1, P-1, a = 11.351(3), b = 11.391(3), c = 11.480(3), α = 112.838(4), β = 90.696(4), γ = 99.328(4); [Zn3(1,4-BDC)3(EtOH)2] 2, C2/c, a = 19.1308(9), b = 10.6088(5), c = 16.2221(7), β = 108.79(1); and [Zn3(1,3-BDC)3(py)2](MeOH) 3, P2(1)/c, a = 17.142(3), b = 21.544(4), c = 11.805(2), β = 106.441(3); TDC = 2,5-thiophenedicarboxylate, BDC = benzedicarboxylate, have been synthesized by linking tri-metal nodes with poly-carboxylate ligands. Single crystal x-ray analysis shows that 1 is composed of (4,4) 2-D grids with A–A stacking while 2 is comprised of (6,3) triangular networks in an A–B–C stacking pattern and 3 has formed a distorted cubic diamondoid topology. Tri-metal nodes are located at the vertexes of each network. Thermal gravimetric analysis demonstrates that 1 and 2 are thermally robust structures with network decomposition temperatures of 375 °C and 460 °C respectively. Tri-metal Secondary Building Units: Toward the Design of Thermally Robust Crystalline Coordination Polymers Brian S. Luisi, Zhenbo Ma and Brian Moulton* Tri-metal nodes are shown to be an advantageous target in the synthesis of 2-D crystalline coordination polymers with high thermal stability.

We report on the supramolecular synthesis and characterization of examples from three series of mixed-ligand coordination complexes composed of copper(II), a drug, and an ancillary ligand (AL). Particularly, we demonstrate how the judicious choice of an ancillary ligand affords a large degree of control over the relative lipophilicity/hydrophilicity of the complex in relation to the uncomplexed drug molecule. Furthermore, we demonstrate several important factors to consider in the design of such complexes such as the additive-constitutive nature of the partition coefficient of the ancillary ligand and the relative size of the two types of ligands.

Reaction of 1,2-bis(2,6-dicarboxypyridin-4-yl)ethyne and imidazole with Cu(II) produces crystals containing a discrete complex of [μ-4,4′-(1,2-ethynediyl)-bis(pyridine-2,6-dicarboxylato)-N, O, O′-μ-N′, O′′, O′′′]-diaqua-bis(imidazole)-dicopper(II) complex (1), [(C16H4N2O8)(C3H4N2)2(H2O)2Cu2] instead of a linear coordination polymer. The complex crystallizes in the monoclinic space group P21/n with a = 5.3763(8) A, b = 18.522(3) A, c = 11.4827(7) A, β = 93.705(3) ° and Z = 2. The complex sits on a center of symmetry such that the two halves of the molecule are related by inversion symmetry. The molecules pack in layers in which the molecules are joined by intermolecular N–H⋯O hydrogen bonds between imidazole and carboxylate groups and O–H⋯O hydrogen bonds between carboxylate groups and water.

Reaction and crystallization of 1,2-bis(2,6-dicarboxypyridin-4-yl)ethyne with Co(II) produces crystals containing monomers of 4-(2,6-dicarboxypyridin-4-yl)ethynylpyridine-2,6-dicarboxylatotriaqua cobalt(II) monohydrate complex (1), [Co(C16H6N2O8)(H2O)3]·H2O, instead of a rigid 1-D metal–organic framework consisting of a linear coordination polymer. This complex crystallizes in the monoclinic space group C2/c with a=6.8028(9) A, b=36.781(5) A, c=7.5135(9) 2.474(2)° and Z=4. The complex sits on a symmetry axis such that the two halves of the molecule are related by two-fold rotation symmetry. The molecules form layers in which the molecules are joined by intermolecular O–H⋯O interactions involving hydrogen bonds between CO2H⋯CO2 −, H2O⋯CO2 −, H2O⋯CO2H and H2O⋯H2O groups.

Reaction of pyrazine-2,3,5,6-tetracarboxylic acid with Cu(II) under hydro(solvo)thermal conditions causes in situ decarboxylation of two carboxyl groups to form pyrazine-2,6-dicarboxylic acid. Coordination of Cu(II) by this ligand generates linear coordination polymers of catena-[diaqua-(μ-pyrazine-2,6-dicarboxylato-N,O,O‘-μ-N‘)copper(II).

The supramolecular chemistry and crystal structures of four bis(imidazolium 2,4,6-tricarboxypyridine) metal(II) trihydrate complexes, where M = Co, Ni, Cu, or Zn (1-Co, 1-Ni, 1-Cu, and 1-Zn, respectively) are reported. Complexes 1-Co, 1-Ni, 1-Cu, and 1-Zn have similar molecular structures that crystallize to give the same packing pattern. 2,4,6-Tricarboxypyridine anions and imidazolium cations form strong N−H···O and O−H···O hydrogen bonds that dominate crystal packing by forming a three-dimensional network of molecules. These complexes form an isomorphous series with a single crystalline architecture that fits at least four different transition metals without changing molecular packing. Thus, these complexes are a family of modular materials in which the organic components define a single packing arrangement that persists over a range of structures and in which the metal serves as a component that can be changed. The molecular and crystal structures of bis(imidazolium 2,4,6-tricarboxypyridine) M(II) comp...

A binuclear manganese(III) complex [Mn2(L1)(N3)6] (2) and an unprecedented 1D chain of manganese(II) binuclear units bridged by two end-to-end thiocyanato anions { [ Mn 2 II ( L 1 ) ( NCS ) 4 ] · 2 CH 3 CN } n (3 · 2CH3CN) have been prepared from N-(1-pyridin-2-ylbenzylidene)-N′-[2-({2-[(1-pyridin-2-ylbenzylidene)amino]ethyl}amino)ethyl]ethane-1,2-diamine (L), manganese(II) salts and azide/thiocyanate anions in air. L1, N-(1-pyridin-2-ylbenzylidene)-N-[2-(4-{2-[(1-pyridin-2-ylbenzylidene)amino]ethyl}piperazin-1-yl)ethyl]amine, results from an alkylating cyclization of the flexible hexadentate Schiff base L occurring along the course of the complexation reactions. Both complexes have been characterized by single crystal X-ray diffraction studies. The Mn centres of complexes 2 and 3 are in distorted octahedral (2: MnIIIN6, 3: MnIIN5S) coordination environments with intramolecular Mn⋯Mn distance (2: 6.473(2) A, 3: 6.437(1) A) consistent with the absence of intramolecular magnetic interactions. Compound 3, exhibits weak intermolecular antiferromagnetic interactions (J = −1.5 cm−1) between pairs of MnII ions bridged via two μ1,3-NCS.

The fundamental precept of crystal engineering is that all the information necessary for the design of a network is already stored in the molecular building blocks used. Coordination polymers represent an example of how crystal engineering has become a paradigm for the synthesis of new architectures and compositions. We report herein ten structures that are supramolecular isomers of one another. The structures are prepared from the same building blocks under mild reaction conditions. The modularity of coordination polymers imparts structural diversity that otherwise would not be possible.

The crystal engineering design strategy facilitates supramolecular synthesis of 13 new crystalline phases of carbamazepine (CBZ), an analgesic and anticonvulsant with known problems related to solubility and polymorphism. CBZ forms supramolecular complexes with the following molecules, all of which are complementary to CBZ in terms of hydrogen bonding and can therefore act as cocrystal formers: acetone (1a); DMSO (1b); benzoquinone (1c); terephthalaldehyde (1d); saccharin (1e); nicotinamide (1f); acetic acid (1g); formic acid (1h); butyric acid (1i); trimesic acid (1j); 5-nitroisophthalic acid (1k); adamantane-1,3,5,7-tetracarboxylic acid (1l); and formamide (1m). Two distinct strategies based upon selection of complementary hydrogen-bond functionalities and previously known supramolecular synthons were utilized: strategy I exploits the exofunctional nature of the carboxamide dimer as either a hydrogen-bond donor or a hydrogen-bond acceptor and thereby retains the carboxamide dimer that is present in al...

The self-assembly of [Cu2(dicarboxylate)2]4 nanoscale secondary building units (nSBUs) into coordination polymers can occur in such a way that a range of calix-like atropisomers can exist. Eight compounds have been prepared and crystallographically characterized via reaction between Cu(NO3)2 and angular dicarboxylate ligands: {[Cu2(bdc)2(py)2]4•guest}n (1a), {[Cu2(bdc)2(py)2]4•4nitrobenzene•2EtOH}n (1b), {[Cu2(bdc)2(4-pic)2]4•4o-dichlorobenzene}n (2), {[Cu2(5-OEt-bdc)2(py)2]4•8H2O}n (3), {[Cu2(5-OPr-bdc)2(py)2]4•guest }n (4), {[Cu2(pdc)2(py)2]4•4MeOH}n (5), {[Cu2(pdc)2(4-pic)2]4•4H2O}n (6), and {[Cu2(tdc)2(MeOH)2]4•4naphthalene•8MeOH}n (7). The following atropisomers, all of which have also been observed in calixarenes, were observed: (a) cone (1a, 3, and 4); (b) partial cone (1b); (c) 1,2-alternate (2 and 5−7); and (d) 1,3-alternate (1a, 3, and 4). The similarities and differences between the crystal structures of 1−7 are detailed herein.

The crystal structure of the 2:1 1,6-diamino-hexane: para-H-calix-4-arene-25,27-di-phosphonate complex shows a designed encapsulation of a calix-arene dimer within a three-dimensional matrix formed by the diamine molecules, the slight mismatch in the length of the diamine molecules compared to the size of the calix-arene molecule is compensated by chain folding in the diamine

Two new binuclear nickel(II) complexes [Ni2L2(NCS)2](ClO4)2 (1) and [Ni2L2(NCO)2](ClO4)2 (2), where L is a pentadentate Schiff base ligand derived from the reaction of 2 mol of 2-benzoyl pyridine and 1 mol of diethylene triamine, have been prepared and characterized. The structures of complexes 1 and 2 have been studied by single crystal X-ray diffraction analysis. The structure analysis reveals that each nickel(II) center is coordinated in a distorted octahedral (NiN6) fashion consisting of three nitrogen atoms from one and two nitrogen atoms from other pentadentate ligand and the last one from terminal thiocyanato/cyanato ion. The variable temperature magnetic susceptibility of both compounds 1 and 2 have been studied and found a very weak magnetic interaction between two nickel(II) centers consistent with the structures (Ni⋯Ni distance of 5.809(1) A for 1 and 5.695(1) A for 2 with no suitable bridge or linkage to propagate magnetic interaction).

To assess the temporal patterns of late gastrointestinal (GI) and genitourinary (GU) radiotherapy toxicity and resolution rates in a randomised controlled trial (All-Ireland Cooperative Oncology Research Group 97-01) assessing duration of neo-adjuvant (NA) hormone therapy for localised prostate cancer.Node negative patients with1 of: PSA20 ng/mL, Gleason score ≥ 7, and stage T3 or more, were included. Follow-up, including toxicity assessment, was three-monthly in the early stages and yearly thereafter.Median follow-up from the end of RT was 6.8 years. In the interval between 90 days following the end of RT and the last toxicity assessment, GI and GU toxicity (any grade) was found in 50% and 51% of 240 and 241 patients, respectively. For those who did develop toxicity, the median time from end of RT until the first development of any grade GI or GU toxicity was 1.2 years and 1.6 years, respectively, whilst median time to final resolution was 1.6 years and 2.2 years, respectively. Grade 2 (G2) or greater GI and GU toxicity occurred in 29 (12.1%) and 40 (16.6%) patients, respectively. The proportion with unresolved G2 + GI and GU toxicity was 89% and 79%, respectively, in year 1, 69% and 65% in year 2, 59% and 52% in year 3 and 27% and 32% in year 5.Long-term toxicities continue to occur many years after NA hormone therapy and RT. The rate of occurrence does not appear to reduce within the time frame during which our patients were followed. The percentage of patients suffering from G2 + toxicity at any time is however low. Resolution of these toxicities continues for the duration of the follow-up.

The synthesis and crystal structures of {[M(4,4′-bipyridine)2(NO3)2]⋅2p-nitroaniline}n, M=Co, 1, Ni, 2, Zn, 3, are described. 1, 2 and 3 crystallize in the form of compounds that can be described as interpenetrating covalent and noncovalent networks. Analysis of the crystal packing in these compounds reveals that the p-nitroaniline molecules form a noncovalent network that is complementary from a topological perspective with [M(4,4′-bipyridine)2(NO3)2] networks, which exist as square grids. These structures are interpreted in the broader perspective of crystal engineering strategies and development of new hybrid materials.

Small rhombihexahedra and small cubicuboctahedra, namely faceted polyhedra, form the basis of two novel low-density framework solids that are afforded by the self-assembly of molecular squares only or molecular squares and triangles, respectively.

The synthesis and crystal structure of [Co(4,4′-bipyridine)2.5(NO3)3]·2C14H10, 1·2C14H10, are presented and discussed in the context of recent developments in the field of coordination polymers. 1 adapts a “molecular railroad” architecture and is closely related to two previously reported molecular railroads in that it contains both bridging and terminal spacer ligands. However, it differs in two important aspects. First, because 1 is uncharged its crystal packing is dominated by stacking interactions between aromatic moieties rather than hydrogen bonding or interpenetration. Second, the resulting open framework planar architecture of 1 sustains coexistence with two topologically complementary sets of phenanthrene molecules. One of these sets can be regarded as a planar network of (4,4) topology whereas the other is an achiral chain of phenanthrene molecules that fills the channels that are generated by the interpenetration of the two planar networks.

The synthesis and crystal structures of [M(4,4′-bipyridine)2(NO3)2]·3naphthalene (M = Co, 1·3naphthalene; Ni, 2·3naphthalene) are reported. 1·3naphthalene and 2·3naphthalene are isostructural and represent rare examples of interpenetrating planar networks that are chemically and topologically different. It appears that the networks coexist because the (4,4) topology of the cobalt and nickel square grids is complementary to the (6,3) topology of the naphthalene honeycomb network, resulting in an inclined interpenetrated 3D architecture. This observation is discussed in the context of rational design strategies for hybrid solids.

A series of crystalline mixed-ligand copper(II)−aspirinate coordination complexes have been synthesized, structurally characterized, and shown to exhibit a diverse range of pharmacologically relevant properties, such as bulk solubility, solubility ratio (Swo/Sow), and partition coefficient.

An unprecedented (8,3)-a 3D coordination network was synthesized using crystal engineering strategies as one of three concomitant supramolecular isomers of the general formula [Cu2(tae)(bipy)2]·2NO...

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma.

A series of bowls separated by hour-glass-shaped channels characterizes the structure of the undulating two-dimensional coordination polymer that is prepared from a nanoscale secondary building unit (nSBU), which is formed by four square metal(II)carboxylate SBUs that have 1,3-benzenedicarboxylate units as 120° spacers.

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We report the first use of fluorescence spectroscopy to probe the environment of the cavities that are present in open framework coordination polymers.

Self-assembly of Zn(NO3)2 with m-pyridinecarboxylate (nicotinate) under mild conditions affords several products including a novel three-dimensional network [Zn(nicotinate)2]n that has connectivity defined by the circuit symbol 4(2).8(4).