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Background: SKLB1039 is a potent, highly selective, and orally bioavailable EZH2 inhibitor, which significantly inhibited breast tumor growth and metastasis in pre-clinical studies. In a previously reported synthesis of SKLB1039, the yields of several steps were low, which led to an overall yield of less than 10%. In addition, flash chromatography was required for the purification of several intermediates using this route. Objective: To optimize the synthesis and establish an efficient commercial-scale method for the production of SKLB1039. Methods: The reaction time, solvent, reactant ratio, temperature, and mode of addition of reactants in the reductive amination, hydrolysis, hexahydroisoquinoline formation, hydrogenolysis, condensation and Suzuki crosscoupling reactions were optimized. Results: A chromatography-free seven-step process starting from a commercially available material was developed that afforded SKLB1039 in 36% overall yield with > 99% purity. Conclusion: A cost-effective, high-yielding, and convergent kilo-scale synthesis for the EZH2 inhibitor SKLB1039 was developed. The operation was simple, and the pure product was easily obtained without column chromatography. This method will be economical and convenient for the subsequent industrial scale-up production of SKLB1039, which will be conducive for this promising EZH2 inhibitor to enter clinical studies of its antitumor effects.

The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound

PRMT6 is a member of the protein arginine methyltransferase family, which is involved in a variety of physiological processes and plays an important role in the occurrence and development of tumors. Due to the high homology of type Ⅰ PRMTs and the two close binding sites of the SAM pocket and the substrate pocket, selective PRMT6 inhibitors have rarely been reported. In this study, a series of (5-phenylpyridin-3-yl)methanamine derivatives were designed and synthesized, which could form hydrogen bonding interactions with the unique Glu49 of PRMT6, thereby improving the selectivity of the compounds for PRMT6. Among them, a25 had the best activity and selectivity, with more than 25-fold selectivity for PRMT1/8 and more than 50-fold selectivity for PRMT3/4/5/7, which was superior to these reported SAM competitive and substrate competitive PRMT6 inhibitors. Importantly, a25 could significantly inhibit the proliferation of various tumor cells and effectively induce apoptosis of cancer cells. Our data clarified that a25 is a promising selective PRMT6 inhibitor for cancer therapy which is worthy of further evaluation.

Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure-activity relationship (SAR) revealed that 12 is a potent Mps1 inhibitor (IC

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound 1 with antituberculosis activity and a minimal inhibitory concentration (MIC) against M. tuberculosis of 20 μg mL−1. Structure optimization and the structure–activity relationship of 1 as the lead compound enabled the design and synthesis of a series of quinolone derivatives, 6a1–6a2, 6b1–6b36, 6c1, 6d1–6d14, 7a1–7a2, 7b1–7b2, 7c1, 8a1–8a5, 9a1–9a4 and 10a1–10a6. These compounds were evaluated in vitro for anti-tubercular activity against the M. tuberculosis H37Rv strain. Among them, compounds 6b6, 6b12 and 6b21 exhibited MIC values in the range of 1.2–3 μg mL−1 and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 μg mL−1, respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 μg mL−1, respectively). In addition, an antibacterial spectrum test carried out using compound 6b21 showed that this compound specifically inhibits M. tuberculosis. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

Enhancer of zeste homologue 2 (EZH2, also known as KMT6A) is found to be a member of the histone lysine methyltransferase family. An increasing number of studies have shown that in addition to methylating histones, EZH2 plays a vital role in a variety of ways. The methylated substrates of EZH2 also include GATA4, AR/AR-related proteins, STAT3, Talin protein, and RORα. Meanwhile, EZH2 has been reported to form complexes with some proteins to perform other important biological functions as well as methylation. These complexes include: the EZH2-RelA-RelB complex, EZH2-ER-β-catenin complex, and β-catenin-PAF-EZH2-Mediator complex. Herein, we focus on the classical and non-classical functions of EZH2, and summarize anti-EZH2 therapeutic strategies. Finally, we highlight that understanding the physiological and pathological functions of EZH2 in specific indications can help the development of inhibitors or degraders.

There is a lack of studies examining the long-term trend and survival of axillary surgery for breast cancer patients with sentinel node metastasis, especially for the patients with 3-5 node metastases.Breast cancer patients with 1-5 sentinel node metastases from the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2016. Our study presented the trend of axillary surgery and assessed the long-term survival of sentinel lymph node biopsy (SLNB) alone vs axillary lymph node dissection (ALND) for those patients.Of the 41,996 patients diagnosed with TFor patients with T

Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure–activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer.

Background: Idiopathic pulmonary fibrosis (IPF) is a lung disease with complex pathogenesis, high mortality. The development of new drugs is time-consuming and laborious, and the research on new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but in recent years it has been found to have other pharmacological effects such as anti-tumor and inhibiting inflammatory diseases related to diabetic nephropathy. However, there are no reports about its role in pulmonary fibrosis.Methods: The therapeutic effect of NIF on bleomycin (BLM)-induced pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, IHC and Western blot. The content of immune cells in lung tissue was analyzed by flow cytometry. NIF cytotoxicity were evaluated in NIH/3T3, Human pulmonary fibroblasts (HPF), A549 and Rat primary lung fibroblasts (RPLF) using MTT assay. Finally, a cell model induced by transforming growth factor-β1 (TGF-β1) stimulation and different in vitro experiments (Immunofluorescence, Western blot, Wound migration assay) were conducted to determine the effect of NIF on the activation of fibroblasts and the epithelial-mesenchymal transition (EMT) and migration of epithelial cells.Results: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by BLM bronchial instillation. In addition, nifuroxazide inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, nifuroxazide suppressed the activation of fibroblasts and the EMT of epithelial cells induced by TGF-β1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that nifuroxazide worked in conjunction with Stat3. Moreover, nifuroxazide decreased the expression of p-Stat3 in vitro and in vivo.Conclusion: These results suggest that NIF inhibits and reverses pulmonary fibrosis and support NIF as a viable treatment option that may bring benefits to patients with IPF.

Objectives Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis. Materials and Methods SKLB‐YTH‐60 was developed through computer‐aided drug design, de novo synthesis and high‐throughput screening. We employed the bleomycin (BLM)‐induced lung fibrosis animal models and used TGF‐β1 to induce the epithelial‐mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α‐smooth muscle actin (α‐SMA), E‐cadherin, p‐FGFR1, p‐PLCγ, p‐Smad2/3 and p‐Erk1/2 was detected by western blot. Results YTH‐60 has obvious anti‐proliferative activity on fibroblasts and A549 cells. Moreover, YTH‐60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF‐β/Smad‐dependent pathways. Intraperitoneal administration of preventive YTH‐60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH‐60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH‐60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half‐life time (T 1/2 = 8.03 hours). Conclusions Taken together, these preclinical evaluations suggested that YTH‐60 could be a promising drug candidate for treating IPF., Schematic model for anti‐fibrotic activity of SKLB‐YTH‐60. In vitro YTH‐60 inhibits the activation of fibroblasts and the EMT of epithelial cells induced by TGFβ1. Intraperitoneal injection of YTH‐60 not only inhibits the bleomycin‐induced lung inflammation, regulates the lung immune microenvironment, but also prevents and reverses pulmonary fibrosis. Finally, the anti‐fibrosis effect of YTH‐60 may be via inhibiting of FGFR and TGF‐β/Smad signaling pathway.

Bromodomain-containing protein 4 (BRD4) has been identified as a potential target in the treatment of many cancers and several BRD4 inhibitors have entered clinical studies. Previous studies have shown that BRD4 degraders have potential to overcome resistance to BRD4 inhibitors. However, most of the BRD4 degraders have poor solubility and bioavailability, one of which the reason is large molecular weight. Here, we describe the design, synthesis, and evaluation studies of a BRD4 degrader based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have led to the discovery of compound 15, which is a weak inhibitor and potent BRD4 degrader with a molecular weight of 821.8. In vitro, 15 can completely degrade BRD4 at nanomolar concentration, with DC50 = 0.25 and 3.15 nM in MV4-11 and RS4-11 cell lines, respectively. Further optimization of compound 15 may reduce its molecular weight and improve druggabillity, and provide a new choice for the treatment of cancer.

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.

The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell–originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPK high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg−1·day−1 dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SKLB-C05 is a specific TOPK inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo.

T–lymphokine-activated killer cell–originated protein kinase (TOPK) is a serine-threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti-cancer activity with IC50s less than 100 nM, superior than reference compound OTS964. The most potent compound, 9g suppressed the growth of cancer cells by apoptosis and specifically inhibited the activities of TOPK. Oral administration of 9g effectively suppressed tumor growth with TGI >79.7% in colorectal cancer xenograft models, demonstrating superior efficacy compared to OTS964. Pharmacokinetic studies reveal its good oral bioavailability. Our findings therefore show that 9g is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic agent against colorectal cancer.

Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.

By targeting the unique Cys663 of EZH2, SKLB-0335 displays high paralog-selectivity on EZH2. Biochemical studies show that SKLB-0335 can covalently bind to EZH2 at its S-adenosylmethionine (SAM) pocket and inhibit H3K27Me3. SKLB-0335 could be an effective chemical probe with which to further investigate the specific biological functions of EZH2.

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC50 = 0.23–1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

Aberrant signaling of fibroblast growth factor receptors (FGFRs) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFRs a compelling target for anticancer therapy. Herein, we describe the design and synthesis of pyrido[1,2-a]pyrimidinone derivatives as potent FGFR inhibitors. Examination of structure–activity relationships and preliminary assessment identified 23d as a novel FGFR inhibitor that displayed excellent potency in vitro. Candidate 23d suppressed the phosphorylation of FGFR signaling pathways and induced cell cycle arrest and apoptosis at low nanomolar concentration. In the kinase inhibition profile, 23d showed excellent kinase selectivity for the FGFR family. Furthermore, 23d showed higher aqueous solubility than Erdafitinib. Moreover, 23d exhibited potent antitumor activity (tumor growth inhibition = 106.4%) in FGFR2-amplified SNU-16 gastric cancer xenograft model using a daily oral dose of 30 mg/kg. These results suggest that 23d is a promising candidate for further drug development.

A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.

Targeting phosphatidylinositol 3-kinase δ (PI3Kδ) is an important therapeutic strategy for indolent non-Hodgkin lymphomas (NHLs). However, we previously observed reactivation of phosphatidylinositol 3-kinase (PI3K) pathways in aggressive NHL cell lines following continuous exposure to PI3Kδ inhibitors (PI3Kδi), which limited their efficacy and suggests that more studies should be focused on this reactivation to improve current PI3Kδi-based treatments. Herein we conducted a drug synergy screening that combined a marketed PI3Kδi, idelalisib, with 14 well-characterized epigenetic drugs across several types of aggressive NHL cell lines. We identified BRD4 inhibitors (BRD4i) as potent partners that, in combination with idelalisib, were capable of synergistically exerting anti-proliferative activity and inducing cell apoptosis in a panel of aggressive NHL cell lines through continuous suppression of PI3K pathways. More importantly, the combination of BRD4i and PI3Kδi simultaneously inhibited transcription and translation of the oncogenic transcription factor c-MYC, downregulating the expression of c-MYC and continuously suppressing the proliferation of cancer cells in vitro, as well as the growth of tumors in vivo even after drug withdrawal. This study, thus, reveals the potential of simultaneously targeting PI3Kδ and BRD4 as a new therapeutic strategy for aggressive forms of NHL.

Polo-like kinase 4 (PLK4), a member of the polo-like kinase family, plays several important roles in mitotic regulation, including centrosome duplication, spindle formation, and cytokinesis. PLK4 overexpression is frequently detected in many human cancers, including ovarian cancer, and the inhibition of PLK4 activity results in cancer cell mitotic arrest and apoptosis. Therefore, PLK4 might be a valid therapeutic target for antitumor therapy. In the present study, we aimed to determine if YLZ-F5, a potent small-molecule inhibitor of PLK4, inhibits ovarian cancer cell growth. MTT assay showed that YLZ-F5 inhibited ovarian cancer cell proliferation in a concentration- and time-dependent manner. The results of colony formation assays were consistent with those of the MTT assay results. In addition, YLZ-F5 induced ovarian cancer cell apoptosis that was associated with activation of caspase-3/caspase-9. Moreover, YLZ-F5 caused aberrant in centriole duplication that was associated with the inhibition of PLK4 phosphorylation. Notably, we showed that YLZ-F5 promoted the accumulation of ovarian cancer cells with mitotic defects (> 4 N DNA content) in a concentration-dependent manner. Furthermore, YLZ-F5 markedly inhibited the migration of A2780 cells. Taken together, these findings suggest that YLZ-F5 is a potential drug candidate for human ovarian cancer.

Amphihevir, a benzofuran derivative, is the first reported hepatitis C virus (HCV) nonstructural protein 4B (NS4B) inhibitor that has advanced to clinical trials (currently in phase Ib trial [CTR20170632]). Here, we report the results of a preclinical study of its potency, toxicity, selectivity, drug metabolism and pharmacokinetics (DMPK), and safety profiles. Amphihevir displayed good antiviral activities against genotype 1a (50% effective concentration [EC(50)] of 0.34 nM) and genotype 1b (EC(50) of 1.97 nM) replicons and no cytotoxicity in 12 cell lines derived from animals and humans. Amphihevir was found to be inactive against other viruses, human kinases, and G protein-coupled receptors (GPCRs), which implies its good selectivity. A 9-day long-term treatment of genotype 1b replicons with amphihevir resulted in a 3.8 Log(10) decline of the hepatitis C viral RNA at a concentration of 25× EC(90). Drug resistance screening showed that mutations occurred at H94, F98, and V105 of NS4B, which mediated the resistance to amphihevir. This result suggests that NS4B is the main target of amphihevir. There was no cross-resistance between amphihevir and NS5A, NS3/4A, and NS5B inhibitors, suggesting that amphihevir in combination with other anti-hepatitis C virus drugs could be used to treat hepatitis C, as proven by studies of amphihevir and other hepatitis C virus inhibitors. Pharmacokinetic studies demonstrated that amphihevir has good oral bioavailability and appropriate half-life (t(1/2)) in rats and dogs, thereby supporting its use once per day. Finally, amphihevir showed good safety profiles in rats and dogs. The results shed light on the use of amphihevir as a potential treatment option for chronic hepatitis C patients.

DspI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, was proposed to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule in the pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study provided a structural basis for the dehydration reaction mechanism of DspI during CDA synthesis. Structural analysis reveals that Glu126, Glu146, Cys127, Cys131 and Cys154 are important for its enzymatic function. Moreover, we show that the deletion of dspI results in a remarkable decreased in the pyoverdine production, flagella-dependent swarming motility, and biofilm dispersion as well as attenuated virulence in P. aeruginosa PA14. This study thus unravels the mechanism of DspI in diffusible signal factor (DSF) CDA biosynthesis, providing vital information for developing inhibitors that interfere with DSF associated pathogenicity in P. aeruginosa.

A palladium catalyzed synthesis of N–H phenanthridinones was developed via C–H arylation. The protocol gives phenanthridinones regioselectively by one-pot reaction without deprotection. It exhibits broad substrate scope and affords targets in up to 95% yields. Importantly, it could be applied for the less reactive o-chlorobenzamides.

New chemotherapeutic compounds and regimens are needed to combat multidrug-resistant Mycobacterium tuberculosis. Here, we used a series of murine models to assess an antitubercular lead compound SKLB-TB1001. In the Mycobacterium bovis bacillus Calmette-Guérin and the acute M. tuberculosis H37Rv infection mouse models, SKLB-TB1001 significantly attenuated the mycobacterial load in lungs and spleens. The colony forming unit counts and histological examination of lungs from H37Rv infected mice revealed that the benzothiazinethione analogue SKLB-TB1001 as a higher dose level was as effective as isoniazid. Moreover, in a multidrug-resistant (MDR)-TB mouse model, SKLB-TB1001 showed significant activity in a dose-dependent manner and was more effective than streptomycin. These results suggested that SKLB-TB1001 could be an antitubercular drug candidate worth further investigation.

Polo-like kinase 4 (PLK4), a vital regulator of centriole duplication, is important for maintaining genome stability. Dysregulation of PLK4 has been found in several human cancers and is associated with a predisposition to tumorigenesis. Herein, we describe the discovery of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as potent PLK4 inhibitors with more concise structure using a scaffold hopping strategy. SAR exploration and preliminary assessment identified 14i as a new PLK4 inhibitor which displayed excellent potency in vitro. 14i could inhibit the activity of PLK4, perturb centriole replication, result in mitosis disorder and induce cell apoptosis in breast cancer cells. Moreover 14i demonstrated significant antitumor efficacy in the MDA-MB-468 and MDA-MB-231 xenograft models. This study suggested that this concise chemotype would represent a promising scaffold of PLK4 inhibitors for cancer therapy and 14i would be an attractive lead compound for further optimization and evaluation.

trans-Arylvinylboronate derivatives are important synthesis blocks in natural products, pharmaceuticals and organic materials. There are only a few reaction conditions that could selectively provide trans-arylvinylboronates by Heck coupling of pinacol vinylboronate and aryl halides. Here we report an efficient and versatile method of palladium catalyzed cross-coupling between pinacol vinylboronate and various aryl or hetaryl bromides to obtain the corresponding trans-(het)arylvinylboronates in excellent yields and selectivity. 30 examples have been synthesized using this protocol which offers an alternative method to prepare these useful building blocks.