Quantitative Structure−Activity Relationship (5D-QSAR) Study of Combretastatin-like Analogues as Inhibitors of Tubulin Assembly

Abstract

A molecular modeling study was carried out to develop a predictive model for combretastatin-like analogues populating the colchicine-binding site of beta-tubulin. A series of compounds built around a framework including two aromatic groups linked by various moieties such as alkenes (stilbenes), enones (chalcones), or ethers was selected for the study. The 5D-QSAR model was developed stepwise. First a model was generated for the chalcone series (19 compounds, 71 conformations), then for the stilbene series (18 compounds, 59 conformations), and finally for the combined dataset (47 ligands, 160 conformers). Although the models for the chalcone and stilbene series appeared slightly different when represented by QSAR colored surfaces, the combined model seems to reconcile the differences without compromise and represents a highly predictive model for compounds that bind to the colchicine-binding site of tubulin.

Highly Potent Triazole-Based Tubulin Polymerization Inhibitors

“…Overall yield 69%; mp 157−159 °C; 1 Methyl-5-[3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazol-4-yl]-indoline (8) Compound 7 (25 mg) was dissolved in 2 mL of HOAc at rt. NaCNBH 3 (1.5 equiv) was added in one portion while stirring, and the solution was stirred overnight.…”

“…The acidic solution was neutralized by adding NaOH solution dropwise and extracted by CHCl 3 . After concentration, the residue was purified by column chromatography with CHCl 3 /MeOH (20:1) as eluent to obtain 20 mg of 7 as a white solid: mp 158−160 °C; 1 Methyl-5-[4-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-1H-indole (9) 5-Iodo-1-methyl-1H-indole (1.0 g, 3.89 mmol) was dissolved in THF (10 mL) and cooled to −10 °C. To the solution was added isopropylmagnesium chloride (2.5 mL, 2.0 M in THF), and the reaction mixture was kept at −10 °C for 30 min.…”

“…Several drops of sulfuric acid were added as catalyst, and the solution was stirred vigorously for 2 h. After neutralization, the alcohol was evaporated and the triazole was purified by column chromatography (EtOAc/hexane 4:1) to obtain 366 mg of triazole with a yield of 71% from thioamide: mp 157−159 °C; 1 …”

“…1 The formation of microtubules is a dynamic process that involves the polymerization and depolymerization of α and β tubulin heterodimers. Molecules binding to tubulins interfere with this dynamic equilibrium and thus induce cell cycle arrest, resulting in cell death.…”

New para–para Stilbenophanes: Synthesis by McMurry Coupling, Conformational Analysis and Inhibition of Tubulin Polymerisation

“…[3] Considerable efforts have been invested in the preparation of analogues of these compounds to unveil the structure-activity relationships and improve the pharmacological profile by increasing the activity and selectivity. [4] In this sense, the prodrug combretaA C H T U N G T R E N N U N G statin A-4 phosphate [5] appears to be a good drug candidate, owing to its vascular disrupting activity and adequate water solubility. Currently, it is in phase II/III clinical trials for the treatment of anaplastic thyroid cancer and solid tumours.…”