Heterocyclizations of pregnenolone: Novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3-b]pyridine derivatives and their cytotoxicity evaluations

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with 4-phenyl-3-thiosemicarbazide gave the thiosemicarbazone derivative 3. The latter compound underwent heterocyclization reactions to give the thiazolyl hydrazonoandrostane and pyrazolyl semicarbazidoandrostane derivatives 5a–d, and 9a–d, respectively. On the other hand compound 1 reacted with either malononitrile or ethyl cyanoacetate to give the Knoevenagel condensated products 11a and 11b, respectively. Compounds 11a,b afforded the thiophenyl pregnane derivatives 12a and 12b, respectively, their reactivity toward some chemical reagents was studied. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference drug, doxorubicin.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Heterocyclization reactions of pregnenolone were studied. ► Structures of the newly synthesized products were confirmed. ► Anti-tumor evaluations of the newly synthesized products against cancer cell lines. ► Pregnenolone derivatives with electron withdrawing substituted groups showed high cytotoxicity.