Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors.

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 β-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-β, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or β (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-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-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) β (S) configuration has a higher score fitness than α (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-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.