Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis
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ORIGINAL PAPER
Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis Bianka Edina Herman1 · János Gardi1 · János Julesz1 · Csaba Tömböly2 · Eszter Szánti‑Pintér3 · Klaudia Fehér3 · Rita Skoda‑Földes3 · Mihály Szécsi1 Received: 12 September 2019 / Accepted: 4 June 2020 © The Author(s) 2020
Abstract The potential inhibitory effect of diverse triazolyl-ferrocene steroids on key enzymes of the estrogen biosynthesis was investigated. Test compounds were synthesized via copper-catalyzed cycloaddition of steroidal azides and ferrocenylalkynes using our efficient methodology published previously. Inhibition of human aromatase, steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activities was investigated with in vitro radiosubstrate incubations. Some of the test compounds were found to be potent inhibitors of the STS. A compound bearing ferrocenyl side chain on the C-2 displayed a reversible inhibition, whereas C-16 and C-17 derivatives displayed competitive irreversible binding mechanism toward the enzyme. 17α-Triazolyl-ferrocene derivatives of 17β-estradiol exerted outstanding inhibitory effect and experiments demonstrated a key role of the ferrocenyl moiety in the enhanced binding affinity. Submicromolar IC50 and Ki parameters enroll these compounds to the group of the most effective STS inhibitors published so far. STS inhibitory potential of the steroidal ferrocenes may lead to the development of novel compounds able to suppress in situ biosynthesis of 17β-estradiol in target tissues. Keywords Steroidal ferrocenes · Estrogen biosynthesis · Steroid sulfatase · Aromatase · 17β-HSD1
Introduction The ferrocene substituent features exceptional biomedical properties. Ferrocene-cinchona hybrids containing a triazole linker were shown to exert antiproliferative effect on Electronic supplementary material The online version of this article (https://doi.org/10.1007/s42977-020-00023-7) contains supplementary material, which is available to authorized users. * Rita Skoda‑Földes [email protected]‑pannon.hu * Mihály Szécsi [email protected]‑szeged.hu 1
1st Department of Medicine, University of Szeged, Korányi fasor 8–10, P. O. Box 427, Szeged 6720, Hungary
2
Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvári körút 62, P. O. Box 521, Szeged 6726, Hungary
3
Department of Organic Chemistry, Institute of Chemistry, University of Pannonia, Egyetem utca 10, P. O. Box 158, Veszprém 8200, Hungary
HepG2 hepatoma and HT-29 colorectal adenocarcinoma human tumor cell lines [20]. Triazole-linked isatin-ferrocene conjugates exhibited selectivity against the hormonedependent (MCF-7) cell line [42]. Steroid-ferrocene hybrids are believed to have a vast potential for medical application [2, 23, 27, 46]. Steroidal ferrocenes were aimed mainly to be applied for vectorization of the DNA damaging effect of the ferrocene entity to produce cytotoxic effect in cancerous cells [18]. C-2, C-16 and C-17
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