Novel D-modified heterocyclic androstane derivatives as potential anticancer agents: Synthesis, characterization, in vitro and in silico studies

Cancer remains a major health concern worldwide. The most frequently diagnosed types of cancer are caused by abnormal production or action of steroid hormones. In the present study, the synthesis and structural characterization of new heterocyclic androstane derivatives with D-homo lactone, 17α-(pyridine-2′′-ylmethyl) or 17(E)-(pyridine-2′′-ylmethylidene) moiety are presented. All compounds were evaluated for their anti-proliferative activity against HeLa cervical cancer cell line and non-cancerous kidney MDCK cells, where A-homo lactam compound 9A showed the greatest selectivity. Based on in vitro binding assays, N-formyl lactam compound 18 appeared to be the strong and isoform-selective ligand for ERα, while compound 9A displayed binding affinity for the GR-LBD, but also inhibited aldo-keto reductase 1C4 enzyme. Out of four selected compounds, methylpyrazolo derivative 13 showed potential for aromatase binding, while in silico studies provided insight into experimentally confirmed protein-ligand interactions. [Display omitted] •New A-homo lactam and A-ring fused pyrazole androstanes were synthesized.•A-Homo lactam derivative appeared to be the most selective for cancer HeLa cells.•N-Formyl lactam compound showed strong and selective binding affinity for ERα.•Only one derivative with pyrazole moiety showed potential as an aromatase inhibitor.•In silico studies support experimentally confirmed protein-ligand interactions.