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

Tijana Lj Šestić; Jovana J Ajduković; Sofija S Bekić; Andjelka S Ćelić; Sanja T Stojanović; Stevo J Najman; Maja A Marinović; Edward T Petri; Dušan Đ Škorić; Marina P Savić

doi:10.1016/j.jsbmb.2023.106362

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

J Steroid Biochem Mol Biol. 2023 Oct:233:106362. doi: 10.1016/j.jsbmb.2023.106362. Epub 2023 Jul 13.

Affiliations

¹ Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
² Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: jovana.ajdukovic@dh.uns.ac.rs.
³ Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 2, 21000 Novi Sad, Serbia.
⁴ Department of Biology and Human Genetics, Faculty of Medicine, University of Niš, 18108 Niš, Serbia; Department for Cell and Tissue Engineering, Scientific Research Center for Biomedicine, Faculty of Medicine, University of Niš, 18108 Niš, Serbia.

PMID: 37451557
DOI: 10.1016/j.jsbmb.2023.106362

Abstract

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.

Keywords: AKR1C4; Anti-proliferative activity; Aromatase; Hormone receptors; Pyrazole, Knorr synthesis; Steroids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androstanes* / chemistry
Androstanes* / pharmacology
Antineoplastic Agents*
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Lactams / pharmacology
Ligands
Molecular Structure
Steroids / metabolism
Structure-Activity Relationship

Substances

Ligands
Androstanes
Steroids
Antineoplastic Agents
Lactams