Han-Yue Qiu

Synthesis and biological evaluation of compounds which contain pyrazole, thiazole and naphthalene ring as antitumor agents

A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a-7a, 1b-7b, 1c-7c, 1d-7d) were firstly synthesized and their anti-proliferative activity, EGFR inhibitory activity, cytotoxicity and inhibition to Hela cell migration were evaluated. Compound 2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) displayed the most potent inhibitory activity (IC50=0.86μM for Hela and IC50=0.12μM for EGFR). Structure-activity relationship (SAR) analysis showed that the anti-proliferative activity was affected by A-ring-substituent (-OCH3>-CH3>-H>-Br>-Cl>-F). Docking simulation of compound 7d into EGFR active site showed that naphthalene ring of 7d with LYS721 formed two p-π bonds, which enhanced antitumor activity. Therefore, compound 7d may be developed as a potential antitumor agent.

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: Design, synthesis, inhibitory activity and 3D-QSAR analysis

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC₅₀ = 23 nM) and 5l (IC₅₀ = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Synthesis and biological evaluation of novel shikonin ester derivatives as potential anti-cancer agents

Shikonin has previously been reported to function as a potent anti-cancer drug that induces cell apoptosis via diverse pathways. To optimize the effectiveness of its pro-apoptotic functions, shikonin was chosen as the best compound for obtaining shikonin ester derivatives (3a–3n) because it possesses an ester group on the side chain hydroxyl position, and the biological activity was evaluated as a potent anti-proliferating inhibitor for many cancer cell lines. Among these compounds, compound 3j exhibited better anti-cancer activities against human hepatocellular carcinoma cell line (HepG2) with an IC50 value of 0.759 μM which was better than that of shikonin which was 1.288 μM. The flow cytometry results showed that compound 3j inhibited the cell growth and caused the cell cycle to be arrested at the G2/M phase. Meanwhile, obvious apoptosis induced by 3j was observed using the Annexin V combined with propidium iodide assay, showing that 3j induced apoptosis of HepG2 cells in a dose and time dependent manner. To investigate the underlying mechanism in the process of apoptosis induced by 3j, the western blot technique was used and the cleavage of caspase-9 was observed but not that of caspase-8. Furthermore, the elevated expression of the p53 protein was positively correlated with the decreased Bcl-2 protein levels and increased Bax protein and the cytochrome C levels. This indicated that the mitochondrial apoptosis pathway directed by p53 responded in the process of apoptosis was induced by 3j. Based on these data, we conclude that compound 3j has the best anti-proliferating and pro-apoptotic effect among the 14 newly synthesized compounds, and it could be a potent candidate for cancer therapy.

Synthesis of aryl dihydrothiazol acyl shikonin ester derivatives as anticancer agents through microtubule stabilization

The high incidence of cancer and the side effects of traditional anticancer drugs motivate the search for new and more effective anticancer drugs. In this study, we synthesized 17 kinds of aryl dihydrothiazol acyl shikonin ester derivatives and evaluated their anticancer activity through MTT assay. Among them, C13 showed better antiproliferation activity with IC50=3.14 ± 0.21 μM against HeLa cells than shikonin (IC50=5.75 ± 0.47 μM). We then performed PI staining assay, cell cycle distribution, and cell apoptosis analysis for C13 and found that it can cause cell arrest in G2/M phase, which leads to cell apoptosis. This derivative can also reduce the adhesive ability of HeLa cells. Docking simulation and confocal microscopy assay results further indicated that C13 could bind well to the tubulin at paclitaxel binding site, leading to tubulin polymerization and mitotic disruption.

Synthesis of dihydropyrazole sulphonamide derivatives that act as anti-cancer agents through COX-2 inhibition.

COX-2 has long been exploited in the treatment of inflammation and relief of pain; however, research increasingly suggests COX-2 inhibitors might possess potential benefits to thwart tumour processes. In the present study, we designed a series of novel COX-2 inhibitors based on analysis of known inhibitors combined with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Derivative 4d was identified as a potent COX-2 enzyme inhibitor and exerted an anticancer effect through COX-2 inhibition. Further investigation confirmed that 4d could induce A549 cell apoptosis and arrest the cell cycle at the G2/M phase. Moreover, treatment with 4d reduced A549 cell adhesive ability and COX-2 expression. The morphological variation of treated cells was also visualized by confocal microscopy. Overall, the biological profile of 4d suggests that this compound may be developed as a potential anticancer agent.

Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9: Design, synthesis, inhibitory activity and 3D-QSAR analysis

New series of sulfonamide derivatives containing a dihydropyrazole moieties inhibitors of MMP-2/MMP-9 were discovered using structure-based drug design. Synthesis, antitumor activity, structure-activity relationship and optimization of physicochemical properties were described. In vitro the bioassay results revealed that most target compounds showed potent inhibitory activity in the enzymatic and cellular assays. Among the compounds, compound 3i exhibited the most potent inhibitory activity with IC50 values of 0.21 μM inhibiting MMP-2 and 1.87 μM inhibiting MMP-9, comparable to the control positive compound CMT-1 (1.26 μM, 2.52 μM). Docking simulation was performed to position compound 3i into the MMP-2 active site to determine the probable binding pose. Docking simulation was further performed to position compound 3i into the MMP-2 active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of MMP-2/MMP-9 inhibitors at present and in future.

Design, synthesis, evaluation and 3D-QSAR analysis of benzosulfonamide benzenesulfonates as potent and selective inhibitors of MMP-2

A novel series of MMPIs was designed, synthesized and purified using a scaffold modification strategy. The new compounds were also evaluated for biological activity against A549, MCF-7, HepG2 and Hela as potential inhibitors of MMP-2. The most potent inhibitor against MMP-2 was compound 19 (IC50 = 0.38 μM). Its antitumor effect is believed to be due to the induction of apoptosis, which is further confirmed by Annexin V-FITC/PI staining assay using flow cytometry analysis. Furthermore, all the compounds were evaluated for cytotoxicity against 293T. In addition, 3D-QSAR studies were conducted. The result showed that the benzosulfonamide benzenesulfonate MMPIs may prove interesting lead candidates to target MMP-2 associated tumor, where the MMP-2 domain is located extracellularly.

Dihydropyrazoles containing morpholine: design, synthesis and bioassay testing as potent antimicrobial agents

A series of dihydropyrazole derivatives containing morpholine was designed and synthesized as antimicrobial agents. All of the synthesized compounds were characterized by 1H-NMR and MS. Afterwards they were evaluated for in vitro antibacterial activity against four bacteria strains. Along with S. aureus TyrRS inhibition and cytotoxicity examination, some compounds proved to be of low toxicity and potent, especially against Gram-positive bacteria strains. Compound 4s exhibited the potential to be new a antibacterial drug with strong broad-spectrum antimicrobial activity and enzyme inhibitory activity. Docking simulation was performed to position compound 4s into the S. aureus TyrRS structure active site to investigate the probable binding mode. A 3D-QSAR model was also established to explain how structural alterations affect the activity and guide further study.

Metronidazole Containing Pyrazole Derivatives Potently Inhibit Tyrosyl‐tRNA Synthetase: Design, Synthesis and Biological Evaluation

As an important enzyme in bacterial protein biosynthesis, tyrosyl‐tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole‐based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram‐negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC = 0.98 μg/mL) and exhibited TryRS inhibitory activity (IC50 = 0.92 μm). Docking simulation was performed to further understand its potency. Membrane‐mediated apoptosis in P. aeruginosa was verified by flow cytometry.

The design, synthesis, in vitro biological evaluation and molecular modeling of novel benzenesulfonate derivatives bearing chalcone moieties as potent anti-microtubulin polymerization agents

A series of novel 3,4-dimethoxylbenzenesulfonate derivatives containing a chalcone structure were synthesized and evaluated for their anti-proliferative activities against HepG2, HCT-116, MCF-7 and HeLa cell lines, as well as the effects of compound 10b on mitotic arrest and cell cycle of MCF-7 carcinoma cell line. Most importantly, the results of DAPI staining under co-focal microscope justified that compound 10b functioned even at relatively low concentration. The analogues showed a potent bio-activity towards tumor cells with IC50 values at nano-mole class, compared with those of positive control drug Colchicine, whose IC50 were 150.4 nM for MCF-7, 123.9 nM for HepG2, 125.4 nM for HCT-116 and 131.4 nM for HeLa cells. Also, a molecular docking modeling was utilized to reveal the binding mode of derivatives and microtubule. Among all the synthesized compounds, compound 10b stands out as IC50 values against all the selected cell lines were at average 80 nM (in which the values against MCF-7 and HepG2 were similar; about 79.2 nM). In this research, we gave strong evidence upon the optimized stratagem for ligands targeting the colchicine-binding site on microtubules, explaining the attribution that the analogues were designed upon the structure of chalcone and combretastatin A-4.