ABSTRACT
A series of aminostilbene-arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from < 0.01 to 19.9 µM. One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of < 0.01 µM. All of the synthesized compounds displayed cytotoxicity against A549 (non-small-cell lung cancer), HeLa (cervical carcinoma), MCF-7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 µM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 µM. Moreover, dot-blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
Subject(s)
Alkenes/chemistry , Drug Design , Stilbenes/chemistry , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin B1/metabolism , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Docking Simulation , Protein Structure, Tertiary , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/toxicityABSTRACT
A new class of hybrid molecules containing cinnamide subunit linked to benzophenone as inhibitors of tubulin polymerization were synthesized and evaluated for their anticancer potential. These hybrids exhibit anticancer activity with IC50 values ranging from 0.06 to 16.3µM. Compounds 4f and 4g possessing fluoro and trifluoromethyl on the cinnamido subunit showed significant cytotoxic activity with IC50 values 0.06 and 0.09µM against HeLa cell line, respectively. These compounds showed cell cycle arrest at G2/M phase of the cell cycle and inhibited tubulin polymerization followed by activation of caspase-3 activity and apoptotic cell death. Further in vitro tubulin polymerization assay showed that the level of tubulin inhibition was comparable to that of 2a for the compounds 4f and 4g. Moreover, Hoechst 33258 staining and DNA fragmentation assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of benzophenone linked cinnamide subunit conjugates as promising anticancer agents with G2/M arrest and apoptotic-inducing ability via targeting tubulin.
Subject(s)
Benzophenones/chemical synthesis , Benzophenones/pharmacology , Cinnamates/chemical synthesis , Cinnamates/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Apoptosis/drug effects , Benzophenones/chemistry , Cell Line, Tumor , Cinnamates/chemistry , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Structure-Activity Relationship , Tubulin Modulators/chemistryABSTRACT
A new class of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine-chalcone conjugates have been prepared by employing a solid-phase synthetic protocol. In this strategy an intramolecular aza-Wittig reductive cyclization approach has been utilized. Interestingly, some of these molecules have shown enhanced DNA-binding affinity and promising anticancer activity on a large number of human cancer cell lines.
