Abstract
Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four beta-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows: (1) trans orientation of the lactone (ring D) with 5a-beta, 8a-alpha configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) alpha (R) or beta (S) configuration has equal fitness in position 5; (5) 4'-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N-2-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6Hpurin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide. All of these structural features are applicable for compounds to fit properly into topoisomerase II, except (1) beta (s) configuration has a higher score fitness than a (R) in position 5; (2) 4'-OH; and (3) position 5 of isoxazolidine ring accommodated better with 6-bromo-9H-purine, 2-amino-6H-purin-6-one or 7H-purin-6-amine. Computational ADMET and toxicity studies were in consensus with the docking results. Compounds holding ethylene bridge between phosphate and benzyl moiety at N-2-position of isoxazolidine ring have the optimal pharmacokinetic properties and were calculated to be non-toxic. The predicted solubility profile for most of 4'-OMe containing compounds was good. This accomplished our aim in identifying promising new hits as antitumor agent with improved activity and less toxicity. (C) 2017 Elsevier Inc. All rights reserved.