A series of 1-benzylidene-3,4-dihydronaphthalen-2-one derivatives were designed and synthesized, and their biological activities in vitro and in vivo were evaluated. The results showed a number of the title compounds exhibiting potent nanomolar activity in several human cancer cell lines. Of these, compound 22b showed the strongest inhibitory activity against human CEM, MDA-MBA-435, and K562 cells (IC(50) = 1 nM), displayed in vitro inhibition of tubulin polymerization (IC(50) = 3.93 μM), and significantly induced cell cycle arrest in G2/M phase. In addition, compound 22b could inhibit the tumor growth in colon nude mouse xenograft tumor model significantly and seemed safer than CA-4 when achieving a similar tumor suppression. This study provided a new molecular scaffold for the further development of antitumor agents that target tubulin.
[Show abstract][Hide abstract] ABSTRACT: A series of new stilbenes 4a-e, 5 were synthesized through a novel one-pot Perkin-like reaction between 6,7-dimethoxyhomophthalic anhydride and aromatic aldehydes, followed by treatment with BBr3. This synthesis is straightforward and allows polyhydroxylated cis-stilbenes gathering two well-known pharmacophoric fragments to be obtained in good yields and for short reaction times. The structure of the newly synthesized compounds was established by spectroscopic methods ((1)H NMR, (13)C NMR, IR and HRMS) and the double bond configuration was unequivocally elucidated by means of gated decoupling (13)C NMR spectra and 2D NOESY experiments. Preliminary differentiating screening of their radical scavenging, antibacterial, anti-fungal and tyrosinase inhibitory activity was further performed. The results obtained suggest that the tested compounds possess a triple biological action as potent radical scavengers, antifungal agents and tyrosinase inhibitors in micromolar concentration. The most promising bioactive compound amongst the others was 4a, acting as excellent radical scavenger against DPPH(•) radical (IC50 ≤ 10 μM), antifungal agent suppressing the growth of Fusarium graminearum (89% inhibition at 0.17 μmol/mL), and tyrosinase inhibitor showing higher activity than hydroquinone at 23 μM.
European Journal of Medicinal Chemistry 06/2013; 66C(51):185-192. DOI:10.1016/j.ejmech.2013.05.040 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of novel (E)-N-aryl-2-arylethenesulfonamides were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound 6t showed dramatic reduction in tumor size indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used anti-mitotic agents. Mechanistic studies indicate that 6t and some other analogs disrupted microtubule formation, formation of mitotic spindles and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin indicating its binding site on tubulin.
[Show abstract][Hide abstract] ABSTRACT: Microtubules are protein biopolymers formed through polymerization of heterodimers of α- and β-tubulins. Disruption of microtubules can induce cell cycle arrest in G2-M phase and formation of abnormal mitotic spindles. Their importance in mitosis and cell division makes microtubules an attractive target for anticancer drug discovery. A number of naturally occurring compounds such as paclitaxel, epothilones, vinblastine, combretastatin, and colchicines exert their effect by changing dynamics of tubulin such as polymerization and depolymerization. During past few years, rapid development of the novel tubulin polymerization inhibitors has been witnessed. Diverse classes of chemical compounds from the natural as well as from the synthetic origin have been extensively studied. This review highlights the various classes of synthetically derived chemical compounds those have been reported in last few years as potential tubulin polymerization inhibitors. A brief synthetic methodology to access these compounds has been highlighted along with the brief SAR studies. We strongly believe that this review will provide a platform to the synthetic chemists and biologists to design and synthesize new and potent compounds to inhibit the tubulin polymerization.
European Journal of Medicinal Chemistry 09/2014; 87C:89-124. DOI:10.1016/j.ejmech.2014.09.051 · 3.45 Impact Factor
Xiao-Dong Yu, Jing-Lei Yang, Wan-Lin Zhang, Dong-Xu Liu
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