Synthesis, anticancer activity and molecular docking studies on 1,2-diarylbenzimidazole analogues as anti-tubulin agents.

Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50 = 0.71-2.41 µM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50 > 100 µM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50 = 8.47 µM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.

Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors.

A series of metronidazole­thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, (1)H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5 e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9 lM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5 a, 5 b, 5 d, 5 e, 5 g and 5 i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.

Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors.

A series of metronidazole-thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, 1H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9µM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.

Synthesis, biological evaluation and molecular modeling of 1,3,4-thiadiazol-2-amide derivatives as novel antitubulin agents.

A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 µM, 0.06 µM and 0.05 µM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50=1.73 µM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.

Synthesis, biological evaluation, and molecular docking studies of novel 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety as FAK inhibitors with anticancer activity.

A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 µM and Hela with IC50 value of 2.54 µM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 µM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.

Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity.

1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 µg/ml and 10.21 µg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 µM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.

Detection Methods and Research Progress of Human Serum Albumin.

Human serum albumin (HSA) is a biological macromolecule with important physiological functions; abnormal HSA levels are associated with coronary heart disease, multiple myeloma, diabetes, nephropathy, neurometabolic disorders, liver cirrhosis and other diseases. Therefore, accurate and quantitative detection of HAS have extremely important research and application value in biological science, molecular biology, clinical medicine and other fields. As for the detection method of HSA, dye-binding method and immune method are the first to be used, and have been applied in clinical detection. In recent years, many new detection technologies have emerged, such as fluorescent probe detection method, nano-materials for HSA detection, biosensor and so on. Although there are many methods developed recently to detect HSA, comprehensive reviews for HSA detection methods are still rare. Thus, writing this review to fill in the blank is in need. In order to highlight the recent progress in the field of HSA detection, in this review, the methods used to detect HSA are summarized and sorted, the advantages and disadvantages of these detection methods are also listed, then the research progress of small molecular fluorescence probe method is emphatically introduced in this paper. Then, we briefly discussed the challenges and future development directions in this field.

Recent Progress in Small Molecular Inhibitors of DNA Gyrase.

BACKGROUND: In the past few decades, with the abuse of antibiotics, bacterial resistance has enhanced constantly. More and more super species of bacteria, which are seriously threatening human health, have been discovered. Developing novel antibacterial agents to overcome the drug-resistance is an urgent duty. We all know that blocking the information-transfer of bacterial DNA and RNA is one of the effective ways to inhibit bacterial growth. Therefore, as the indispensable enzyme for DNA replication and transcription, DNA gyrase is one of the important targets for bacterial inhibitors. Accordingly, many inhibitors of DNA gyrase have also been developed. METHODS: In this review, to highlight the recent progress in DNA gyrase inhibitors, the study in this field over the past three years (2017-2019) was summarized and organized based on their backbones or core moieties. Both of the subunits of DNA gyrase were taken into consideration. RESULTS: These DNA gyrase inhibitors have been classified based on their backbones or core moieties. After the comparison of the divided 14 categories, we could achieve some clues for future modification. In particular, we found that benzodiazepines and naphthalene heterocycles were the most common structures in the drug design. On the other hand, isopropyl and cyclopropyl have also been used in drug design, which provides more inspiration for the investigations. Except for GSK2140944, which has entered the phase III clinical trial stage, other compounds here were not fully promulgated with their optimal pharmacokinetic activity. CONCLUSION: We briefly summed up the current situation and future challenges on this topic. Through the discussion of the design strategies and drug effect, we hope that this review can provide a focused direction for future researches.

A patent review of RAF kinase inhibitors (2010-2018).

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.

A class of novel tubulin polymerization inhibitors exert effective anti-tumor activity via mitotic catastrophe.

In current work, a class of novel 4,5-dihydro-1H-pyrazole-1-carboxylate derivatives (E01-E28) were designed, synthesized and evaluated. Among them, the most potent compound E24 exhibited comparable activity against a panel of cancer cells (GI50 ranging 0.05-0.98 µM) and tubulin polymerization inhibition (IC50 = 1.49 µM) with reference drug CA-4(P) (GI50 ranging 0.019-0.32 µM, IC50 = 2.18 µM). The following assays indicated that compound E24 disturbed the dynamics of tubulin catastrophe and rescue, which triggered G2/M arrest, leading to ROS accumulation, cleavage of PARP and apoptosis. Molecular dynamics simulation validated that compound E24 could tightly bind into tubulin heterodimers with ß Lys 254 and ß Cys 241 of tubulin in the docking pose. Metabolic stability and pharmacokinetics parameters were also determined. The half time (t1/2) displayed species differences in three microsomes. The plasma elimination half-life (t1/2), peak plasma concentration (Cmax), mean retention time (MRT), the area under the curve (AUC0-∞) and distribution volume (Vz) of E24 after intravenous administration were 0.90 ± 0.22 h, 594.50 ± 97.23 ng/mL, 1.09 ± 0.22 h, 413.67 ± 105.64 ng/mL*h and 5.03 ± 1.82 L/kg, respectively. In HeLa-xenografts, compound E24 exhibited obvious antitumor efficacy via the suppression of tumor growth without weight loss of body or organ. In brief, compound E24 might be a hopeful candidate with excellent properties for oncotherapy as tubulin polymerization inhibitor.

FAK inhibitors in Cancer, a patent review.

INTRODUCTION: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates signalling events downstream of integrin engagement of the ECM. FAK is known to regulate cell survival, proliferation and migration. AREAS COVERED: FAK expression has also been shown to be up-regulated in many cancer types. Previous study also indicates that FAK-mediated signaling and functions are intrinsically involved in the progression of tumor aggressiveness, suggesting that FAK is a promising target for anticancer therapies. Small molecule FAK inhibitors have been developed and are being tested in clinical phase trials. EXPERT OPINION: These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. In this review, we give updates on the design, synthesis and structure-activity relationship analysis of small molecule FAK inhibitors discovered from 2015 until now. We also review the FAK inhibitors that are in clinical development and highlight the future prospects.

Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitors.

A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 = 0.07 µM, 0.05 µM, 0.03 µM, respectively) and the tubulin polymerization inhibitory activity (IC50 = 1.88 µM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin.