Discovery of potent tubulin inhibitors targeting the colchicine binding site via structure-based lead optimization and antitumor evaluation

Abstract

The colchicine binding site of tubulin is a promising target for discovering novel antitumour agents. Previously, we identified 2-aryl-4-amide-quinoline derivatives displayed moderate tubulin polymerisation inhibitory activity and broad-spectrum in vitro antitumour activity. In this study, structure based rational design and systematic structural optimisation were performed to obtain analogues C1∼J2 bearing diverse substituents and scaffolds. Among them, analogue G13 bearing a hydroxymethyl group displayed good tubulin polymerisation inhibitory activity (IC 50 = 13.5 μM) and potent antiproliferative activity (IC 50 values: 0.65 μM∼0.90 μM). G13 potently inhibited the migration and invasion of MDA-MB-231 cells, and displayed potent antiangiogenic activity. It efficiently increased intracellular ROS level and decreased MMP in cancer cells, and obviously induced the fragmentation and disassembly of the microtubules network. More importantly, G13 exhibited good in vivo antitumour efficacy in MDA-MB-231 xenograft model (TGI = 38.2%; i.p., 30 mg/kg).

Discovery of PlatinumIV–Artesunate Multiaction Prodrugs as Potent Antitumor and Antimalarial Agents

“…I n vitro antitumor activity was conducted using the CCK-8 method. − The solid tumor cell lines HepG2 (liver cancer cell), A549 (lung cancer cell), HCT116 (colon cancer cell), MDA-MB-231 (triple-negative breast cancer cell), and CDDP-resistant A549 (A549/CDDP) were used in this study. CDDP, ATS, and the mixture (ATS plus CDDP, 1:1) were used as the positive control.…”

Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors

“…2,3 Tubulin proteins are well-verified targets for anticancer therapy. [4][5][6][7][8][9][10] Microtubules consisting of tubulin polymers are involved in cell growth, division, motility, and intracellular transport. [10][11][12][13] Microtubule-targeting agents interfere with tubulin polymerization/depolymerization processes, disrupt the process of cell division, evoke cell cycle arrest, and eventually lead to cell apoptosis.…”