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 ferrocenyl-alkynes 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.
Highlights
The ferrocene substituent features exceptional biomedical properties
Aromatase inhibition was tested by the transformation of testosterone to 17β-estradiol, and STS inhibition was investigated via hydrolytic release of estrone from estrone-3-sulfate, whereas the influence on 17β-HSD1 was measured on estrone to 17β-estradiol conversion
We investigated in vitro inhibitory effects of ten diverse steroidal ferrocene substances exerted on key enzymes of the estrogen biosynthesis
Summary
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 ferrocene derivatives of androgens as well as C-3, C-7, C-16 and C-17 ferrocene derivatives of 17β-estradiol and estrone demonstrated considerable antiproliferative effects (micromolar IC50 or GI50 values) against hormone-independent cancerous cell lines [18, 23, 49, 51, 53]. Potential inhibitory effect of the ferrocene steroid
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