Novel Microtubule Polymerization Inhibitor with Potent Antiproliferative and Antitumor Activity

Abstract

Microtubule-stabilizing and microtubule-destabilizing agents are commonly used as anticancer agents. Although highly effective, success with these agents has been limited due to their relative insolubility, cumbersome synthesis/purification, toxic side effects, and development of multidrug resistance. Hence, the identification of improved agents that circumvent one or more of these problems is warranted. We recently described the rational design of a series of triazole-based compounds as antimitotic agents. Members of this Nsubstituted 1,2,4-triazole family of compounds exhibit potent tubulin polymerization inhibition and broad spectrum cellular cytotoxicity. Here, we extensively characterize the in vitro and in vivo effects of our lead compound from the series 1-methyl-5-(3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-4-yl)-1H-indole, designated T115. We show that T115 competes with colchicine for its binding pocket in tubulin, produces robust inhibition of tubulin polymerization, and disrupts the microtubule network system inside the cells. In addition, T115 arrests human cancer cells in the G 2 -M phase of cell cycling, a hallmark of microtubule destabilizing drugs. T115 also inhibits cell viability of several cancer cell lines, including multidrug-resistant cell lines, in the low nanomolar range. No cytotoxicity was observed by T115 against normal human skin fibroblasts cell lines, and acute toxicity studies in normal nontumor-bearing mice indicated that T115 is well-tolerated in vivo (maximum total tolerated dose, 400 mg/kg). In a mouse xenograft model using human colorectal (HT-29) and prostate (PC3) cancer cells, T115 significantly inhibited tumor growth when administered i.p. Taken together, our results suggest that T115 is a potential drug candidate for cancer chemotherapy.

Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

“…To assess the generality of this conclusion, we extended the experiments to HT29 colorectal adenocarcinoma cell lines, a widely used cellular model for its sensitivity to classical MT-inhibitory drugs [54]. …”

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

“…Therefore, the discovery of potential microtubule inhibitors is an attractive strategy for cancer therapy. Further, tubulin-targeting compounds including taxanes, vinca alkaloids, and combretastatins have been widely used in the treatment of many cancers [111,112]. The poor bioavailability and multidrug resistance of these drugs compel researchers to exploit novel inhibitors toward microtubule polymerization with low side effect, little drug resistance, and good oral activity [113,114].…”

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

“…In a mouse xenograft model using HT-29 human colon carcinoma or PC3 prostate cancer cells, a significant inhibition of tumor growth was observed after intraperitoneal administration. 55 Among nonaromatic heterocycles bridging rings A and B, the 2-azetidinones (β-lactams), described by Sun et al, 56 have been proposed as a viable linking alternative. Indeed, compound 19 57 ( Figure 6) has shown antiproliferative activity in the sub-nM range and new compounds in this series still continue to be explored.…”

“…A superposition of their binding modes can be seen in Figure 16b. The second group collects a number of ligands (40,48,55,56, and 58, Figure 13) that mimic the binding of the pyrrolidinedione 53, occupying zones 2 and 3, and whose superpositions are shown in Figure 16c. When comparing the superposition in Figure 16b,c, it could be argued that planar compounds tend to locate deeper into the β-subunit making use of zones 2 and 3, whereas more globular or butterfly like shaped ligands occupy zones 1 and 2, mimicking the colchicine-binding mode.…”