Synthesis and Antiproliferative Activity of 4β‐O‐Substituted, 4β‐N‐Substituted Deoxypodophyllotoxin Derivatives, and 4β‐OH‐ 4’‐O‐Substituted Podophyllotoxin

Abstract

Podophyllotoxin (PPT) and its derivatives possess various biological activities and particularly against numerous cancers. The high toxicity and side effects of this therapeutic class are behind the restricted deployment in clinical applications. Here, we have identified and reported the synthesis of 4β‐O‐substituted 4’‐O‐demethylpodphyllotoxin derivatives, 4β‐N‐substituted 4’‐O‐demethyl‐4‐ deoxypodophyllotoxin derivatives and 4β‐OH‐ 4’‐O‐substituted podophyllotoxin derivative (series a, e and p) respectively. These derivatives are either esters or amides of various heterocyclic moieties which include imidazole, thiazole, pyrazole, and indole. Their synthesis was carried out in one step reaction and obtained in good yield. We tested all prepared compounds against T47D, MDA231, Caco‐2, and MCF‐7 cancer cell lines. They have been shown to possess significant biological activity, where series “a” has been demonstrated to be the most potent one. Compound 3 a exhibits potential activity in the micromolar range scoring 11 μM against Caco‐2 and 18 μM against MDA231. Consequently, all synthesized compounds have been evaluated for their safety profile and tested against PCS201012 which are normal skin fibroblast cell lines showing noticeable safety. The biological results demonstrate that the presence of an aromatic heterocycle ring in position 4 and 4’ lead to derivatives less toxic compared to podophyllotoxin and epipodophyllotoxin. Also, they are less potent. However, the results obtained will have, in future work, an important impact on the development of more potent and less toxic leads.