4-O-Podophyllotoxin sulfamate derivatives were prepared using the natural lignan podophyllotoxin. The prepared compounds were afforded by reacting O-sulfonyl chloride podophyllotoxin with ammonia or aminoaryl/heteroaryl motif. Biological evaluation was performed in human breast cancer (MCF7), ovarian cancer (A2780), colon adenocarcinoma (HT29), and normal lung fibroblast (MRC5) cell lines. Compound 3 exhibited potent inhibitory activity and good selectivity margin. Compounds 2, 3, and 7 exerted apoptotic effect in MCF7 cells in a dose-dependent manner. The cytotoxicity of the verified compounds was inferior to that of podophyllotoxin.

Cancer is one of the leading causes of death worldwide, and it has a major impact on public health. Phosphatidylinositol 3‐kinase (PI3Kα) has been recognized as a promising drug target for developing anticancer agents. Herein, a series of N‐phenyl‐6‐fluoro‐4‐hydroxy‐2‐quinolone‐3‐carboxamides was developed to target PI3Kα. All synthesized compounds were characterized using FT‐IR, NMR (1H and 13C) and elemental analysis. All synthesized chemical analogues exerted distinctive anticancer activity. They inhibited the growth of human epithelial colorectal adenocarcinoma (Caco‐2) with IC50 values between 48.63–378 μM, and human colon cancer (HCT‐116) cell lines with IC50 values between 44–664 μM. Computational modelling studies provided important biological insight. Induced‐fit docking (IFD) studies showed that the synthesized chemical analogues fit the kinase catalytic domains and form a significant H‐bond interaction network with key amino acids at the biding site. Furthermore, cheminformatics analyses indicated that all synthesized compounds were drug‐like permitting further animal testing or clinical development.

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.