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. Issue 214 (November 2021)

• Record Type: Journal Article
• Authors: Kulmány, Ágnes Erika; Herman, Bianka Edina; Zupkó, István; Sinreih, Masa; Rižner, Tea Lanišnik; Savić, Marina; Oklješa, Aleksandar; Nikolić, Andrea; Nagy, Viktória; Ocsovszki, Imre; Szécsi, Mihály; Jovanović-Šanta, Suzana
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 214(2021)
• Publication Date: 2021-11
• Subjects: Estrone- and androstane-derived heterosteroids -- Microwave-assisted synthesis -- Steroidogenic enzyme inhibition -- Cytotoxicity -- Steroidogenesis enzyme genes expression; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2021.105997
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: d -ring–modified heterocyclic steroids are synthesized by microwave-assisted reactions. d -ring–fused triazole estrone analog, compound 24, inhibits 17β-HSD1 activity. Compound 24 induces cell-cycle changes and apoptosis in HeLa, SiHa, MDA-MB-231 cells. Compound 24 increases mRNA expression of SULT1E1 and shows anti-estrogen potential. Compound 24 shows a pharmacological potential. 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.