Combretastatin-Inspired Heterocycles as Antitubulin Anticancer Agents

Abstract

Combretastatin (CA-4) and its analogues are undergoing several clinical trials for treating different types of tumors. In this work, the antiproliferative activity of a series of 2-aminoimidazole-carbonyl analogs of clinically relevant combretastatins A-4 (CA-4) and A-1 was evaluated using a cell-based assay. Among the compounds tested, C-13 and C-21 displayed strong antiproliferative activities against HeLa cells. C-13 inhibited the proliferation of lung carcinoma (A549) cells more potently than combretastatin A-4. C-13 also retarded the migration of A549 cells. Interestingly, C-13 displayed much stronger antiproliferative effects against breast carcinoma and skin melanoma cells compared to noncancerous breast epithelial and skin fibroblast cells. C-13 strongly disassembled cellular microtubules, perturbed the localization of EB1 protein, inhibited mitosis in cultured cells, and bound to tubulin at the colchicine site and inhibited the polymerization of reconstituted microtubules in vitro. C-13 treatment increased the level of reactive oxygen species and induced apoptosis via poly(ADP-ribose) polymerase-cleavage in HeLa cells. The results revealed the importance of the 2-aminoimidazole-carbonyl motif as a double bond replacement in combretastatin and indicated a pharmacodynamically interesting pattern of H-bond acceptors/donors and requisite syn-templated aryls.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…The microtubule targeting agents (MTAs) bind to the complex three-dimensional surface of the tubulin polymer and exhibit antiproliferative activity. MTAs exert their effects as microtubule stabilizers or polymerizing agents [59,61,62]. Paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, and vindesine are highly effective anticancer agents acting as microtubule-targeting [62].…”

“…MTAs exert their effects as microtubule stabilizers or polymerizing agents [59,61,62]. Paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, and vindesine are highly effective anticancer agents acting as microtubule-targeting [62]. Paclitaxel, docetaxel and the polyisoprenyl benzophenones effect as polymerizing agents while colchicine, vinblastine, and vincristine as depolymerizing agents [59].…”

“…Paclitaxel, docetaxel and the polyisoprenyl benzophenones effect as polymerizing agents while colchicine, vinblastine, and vincristine as depolymerizing agents [59]. In addition to these natural products, several natural products such as combretastatins, epothilones, dolastatins, and 2-methoxyestradiol are in clinical trials for cancer chemotherapy [62] (Figure 9). Combretastatins bind at the colchicine binding site on the β-tubulin subunit of tubulin and cause depolymerization of tubulin, which is known to be separate from the vinca binding site [18,59,62].…”

“…In addition to these natural products, several natural products such as combretastatins, epothilones, dolastatins, and 2-methoxyestradiol are in clinical trials for cancer chemotherapy [62] (Figure 9). Combretastatins bind at the colchicine binding site on the β-tubulin subunit of tubulin and cause depolymerization of tubulin, which is known to be separate from the vinca binding site [18,59,62]. Recent studies on some types of MTAs revealed that colchicine site binding drugs such as the combretastatins can inhibit the formation of new blood vessels in cancer tissue selectively as vascular disrupting agents (VDAs) [61,63].…”

Design and Synthesis of New Tubulin Polymerization Inhibitors Inspired from Combretastatin A‐4: An Anticancer Agent

“…Earlier reported synthetic derivatives of CA-4 also had retained the original anti-tubulin target specificity. [22][23][24][25][26][27][28][29][30][31][32][33][34][35] The isoxazoline and 1, 2, 3-triazole are enriched with lone pair of electrons along with pi electrons in the double bonds which impart noncovalent interactions. Both moieties show biological potential with a plethora of pharmacological effects on varying connecting molecular-skeletal combinations.…”