Zhong-Chang Wang

Coumarin sulfonamides derivatives as potent and selective COX-2 inhibitors with efficacy in suppressing cancer proliferation and metastasis

Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09μM for COX-2, IC50=48.20μM for COX-1, IC50=0.36μM against HeLa cells), comparable to the control positive compound Celecoxib (0.31μM, 43.37μM, 7.79μM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.

Icariin promotes histone acetylation and attenuates post-stroke cognitive impairment in the central cholinergic circuits of mice.

Post-stroke dementia (PSD) is a common clinical disease and the central cholinergic circuits are important to cognitive function. Icariin (ICA), a flavonoid isolated from Herba Epimedii, was reported to improve cognitive function through modulating the cholinergic system. But there were no studies exploring the role of ICA in PSD animal models. In this study, we used transient middle cerebral artery occlusion mice with cognitive dysfunction in the PSD model. PSD mice were then randomly divided into six groups: Sham-operated+placebo group, Sham-operated+ICA group (60mg/kg), PSD model+placebo group, PSD model+ICA group (30, 60, or 120mg/kg). We observed spatial learning ability and memory by Morris water maze test. The levels of acetylcholine (ACH) and choline acetyltransferase (ChAT), the degree of histone acetylation and the cAMP response element-binding protein (CREB) phosphorylation in the central cholinergic circuits were investigated by Western blot and immunofluorescence. After the administration of various doses of ICA, the escape latency and searching distance of the PSD mice were reduced significantly compared with those without ICA treatment. While the levels of ACH and ChAT declined, the degree of histone acetylation and the CREB phosphorylation was improved in a dose-dependent manner in central cholinergic circuits. In conclusion, ICA can improve post-stroke dementia, and the mechanism is likely to enhance CREB phosphorylation in the central cholinergic circuits, thus improving the damage in cholinergic circuits histone acetylation homeostasis.

Design, synthesis, biological evaluation and molecular modeling of dihydropyrazole sulfonamide derivatives as potential COX-1/COX-2 inhibitors.

Novel dihydropyrazole sulfonamide derivatives (30-56) were designed, synthesized, and evaluated for their biological activities as COX-1 and COX-2 inhibitors. In vitro biological evaluation against three human tumor cell lines revealed that most target compounds showed antiproliferative activities. Among the compounds, compound 48 exhibited the most potent and selective COX-2 inhibitor (COX-2 IC50=0.33 μM; COX-1 IC50=68.49 μM) relative to the reference drugs celecoxib (IC50=0.052 μM). Docking simulation was performed to position compound 48 into the COX-2 active site and the result showed that compound 48 could bind well at the COX-2 active site and it indicated that compound 48 could be a potent and selective COX-2 inhibitor.

Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors

A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 μM for MCF-7 and IC(50) = 0.45 μM for WM266.5, IC(50) = 0.22 μM for BRAF(V600E), 3m: IC(50) = 0.97 μM for MCF-7 and IC(50) = 0.72 μM for WM266.5, IC(50) = 0.46 μM for BRAF(V600E), which were comparable with the positive control Erlotinib.

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 docking studies of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives as novel antitubulin agents.

A series of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives (1h-20h) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 2h showed the most potent activity in vitro, which inhibited the growth of MCF-7, Hep-G2 and A549 cell lines with IC(50) values of 0.70 ± 0.05, 0.68 ± 0.02 and 0.86 ± 0.05 μM, respectively. Compound 2h also exhibited significant tubulin polymerization inhibitory activity (IC(50)=3.06 ± 0.05 μM). The result of flow cytometry (FCM) demonstrated that compound 2h induced cell apoptosis. Docking simulation was performed to insert compound 2h into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 2h with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Design, Synthesis and Antitumor Activity of Novel link-bridge and B-Ring Modified Combretastatin A-4 (CA-4) Analogues as Potent Antitubulin Agents.

A series of 12 novel acylhydrazone, chalcone and amide–bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, 1H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.

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.

Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: design, synthesis and biology analysis.

A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 μM. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage.