Heterocyclic androstane and estrane d-ring modified steroids: Microwave-assisted synthesis, steroid-converting enzyme inhibition, apoptosis induction, and effects on genes encoding estrogen inactivating enzymes.

Abstract

d-ring-fused and d-homo lactone compounds in estratriene and androstane series were synthesized using microwave-assisted reaction conditions. Microwave-irradiated synthesis methods were convenient and effective, and provided high yields with short reaction times. Their inhibition of C17,20-lyase and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activities were studied in in vitro enzyme assays. d-ring-fused triazolyl estrone analog 24 showed potent inhibition of NADH-complexed 17β-HSD1, with a binding affinity similar to that of the substrate estrone; its inhibition against NADPH-complexed 17β-HSD1 was markedly weaker. Compound 24 also significantly and selectively reduced proliferation of cancer cell lines of gynecological origin. This estrane triazole changed the cell cycle and induced apoptosis of HeLa, SiHa, and MDA-MB-231 cancer cells, measured by both increased subG1 fraction of cells and activation of caspase-independent signaling pathways. A third mode of anti-estrogenic action of 24 saw increased mRNA expression of the SULT1E1 gene in HeLa cells; in contrast, its 3-benzyloxy analog 23 increased mRNA expression of the HSD17B2 gene, thus showing pronounced pro-drug anti-estrogenic activity. Estradiol-derived d-ring triazole compound 24 thus acts at the enzyme, gene expression and cellular levels to decrease the production of active estrogen hormones, demonstrating its pharmacological potential.

• Authors: Ágnes Erika Kulmány, Bianka Edina Herman, István Zupkó, Masa Sinreih, Tea Lanišnik Rižner, Marina Savić, Aleksandar Oklješa, Andrea Nikolić, Viktória Nagy, Imre Ocsovszki, Mihály Szécsi, Suzana Jovanović-Šanta
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 214 Pg. 105997 (11 2021) ISSN: 1879-1220 [Electronic] England
• PMID: 34509617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Androstanes
• Enzyme Inhibitors
• Estranes
• Estrogens
• Fatty Acids
• IDS 89 Sabal serrulata extract
• Phytosterols
• RNA, Messenger
• Estrone
• Estradiol
• RNA

Topics

• Androstanes (metabolism)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Enzyme Inhibitors (pharmacology)
• Estradiol (pharmacology)
• Estranes (metabolism)
• Estrogens (pharmacology)
• Estrone (pharmacology)
• Fatty Acids (metabolism)
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Microwaves
• Phytosterols (metabolism)
• RNA (analysis)
• RNA, Messenger (metabolism)
• Signal Transduction