Synthesis of ferrocene-labelled steroid derivatives via homogeneous catalytic methods (original) (raw)
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Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis
Biologia Futura
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 IC50andKiparameters enroll these compounds to th...
Applied Organometallic Chemistry
Conjugates of ferrocene with steroidal estrogens as selective antiproliferative agents against hormone-dependent breast cancer cells are believed to be limited by the inherent estrogenicity of the conjugates. Motivated by a significant cytotoxicity of the ester of ferrocenecarboxylic acid and the phenolic group of estradiol toward such a cell line, we decided to explore other A-ring-tethered ferrocene-estra-1,3,5(10)-triene conjugates; in this study, ferrocenylmethylation of estradiol and estrone with (ferrocenylmethyl) trimethylammonium iodide in the presence of potassium carbonate yielded five new compounds (1-5). In dimethylformamide, only O-alkylated products formed (1 and 3), while a mixture of O-and C-alkylated products was obtained when methanol was used (2, 4, and 5 in addition to 1 and 3). All compounds were characterized using 1D and 2D NMR, IR, UV-Vis, and high-resolution mass spectrometry. Two of the conjugates, a 3-O-and a 4-Calkylated derivative of estrone (3 and 4, respectively), were also analyzed using single-crystal X-ray diffraction. A cyclic voltammetric investigation of the electrochemical properties of 1-5 was performed. While some of the compounds were shown to have a slight-to-moderate antiproliferative activity against at least one of the six tested human tumor cell lines and were nontoxic to (the noncancerous) fetal human fibroblasts, compound 2 (4-(ferrocenylmethyl)estra-1,3,5(10)-triene-3,17β-diol) with an IC 50 value of 0.34 μM was found to be more active against the hormone-dependent breast cancer cell line MCF-7 than doxorubicin. These results suggest that A-ring substitution of steroidal estrogens is a plausible strategy for preparing other ferrocene-steroid conjugates acting against tumor cells.
Oriental Journal of Chemistry, 2017
Several steroid-pyrrole derivatives have been prepared using different protocols; nevertheless, have some drawbacks such as the use of some reagents that have limited stability and require special conditions. The aim of study involved the synthesis of two steroid-pyrrolo-triazecin derivatives using a series of reactions that involve; cycloaddition [2 + 2], displacement of nitro group, formation of shift base, amidation/cyclization using boric acid (Method A) or carbodiimide derivative (Method B). The results showed that there is a higher yielding with the method A in comparison with the method B. In addition, chemical structure of compounds was confirmed by NMR spectroscopic data.
The Journal of Organic Chemistry, 1990
Reduction of the 20-keto group of both l7a-hydroxy-and 16a-alkoxy-17a-hydroxy steroids has been examined with various hydride reagents in a number of different solvent systems. For each of these steroids, specific conditions have been established to cleanly reduce to (2OR)-17a,2@a-diob. These conditions have been applied to the synthesis of (E)-3p-hydroxy-5,17(2O)-pregnadiene 3-pivaloate (5) and (Z)-3/3,16a-dihydroxy-5,17(20)-pregnadiene 3-pivaloate (6) from commercially available 3&17a-dihydroxy-5-pregnen-20-one (7a) and 3/3-hydroxy-5,16-pregnadien-20-one (1 la), respectively. The pivaloate derivative of 7a was reduced with L-Selectride in THF to provide, after mild acid treatment and oxidative workup, (20R)-17a,20-diol 9 as a single stereoisomer in 86% yield. Subsequent syn-dideoxygenation of its thionocarbonate derivative with triethyl phosphite afforded pure (E)-ethylidene 5 in 56% overall yield from 7a. [2-(Trimethylsilyl)ethoxy]methyl (SEM) ether derivative of the 16a-hydroxy group of 3/3,16a,l7a-trihydroxy-5-pregnen-20-one 3-pivaloate (13b), obtained in two steps from 1 la, was reduced with (~-B U)~N B H~ in THF to provide, after mild acid treatment of the quenched solution, (20R)-17a,20-diol 14b as a single stereoisomer in 90% yield. Similar dideoxygenation of the diol followed by deprotection of the SEM group with CsF gave 16a-hydroxylated (Z)-17-ethylidene 6 in 48% overall yield from lla. In addition, results on stereoselective syn-deoxygenation of (20s)-17a,20-epoxides are also discussed. Stereochemically pure 17-ethylidene steroids'$ and their 16-oxygenated analogues'J are pivotal intermediates for the stereocontrolled construction of steroid side chains. While (a-17-ethylidene l2 and its lea-hydroxylated derivative (E isomer) z3 are obtainable stereoselectively, their geometric isomers 3 and 4 are not as readily accessible at present. A variety of multistep approaches toward 3 are described in the literature, often without experimental procedure^.^ Among these, the best method appears to be a six-step synthesis of (E)-3P-hydroxy-5,17(20)-pregnadiene tetrahydropyranyl ether from dehydroisoandrosterone reported by Midland.lg In contrast, the only available means to access its 16a-hydroxylated analogue 4 is either through laborious chromatographic separation of the minor component of the product mixture obtained from the Wharton reaction5a of 16a,17a-epoxy-20-one
Ferrocene and titanocene steroid conjugates: Structures and activities – a brief review
The present review describes the biological activities of ferrocenes and titanocenes steroid conjugates. Ferrocenes steroid conjugates demonstrate antineoplastic and antihypercholesterolemic activity with a confidence more than 90 percent, and can be used as erythropoiesis-stimulating agents. Titanocenes steroid conjugates show anti-inflammatory and anti-seborrheic activity with a confidence more than 70 percent, and can also be used as glutaconyl-CoA decarboxylase inhibitors and/or erythropoiesis-stimulating agents. With the computer programme PASS and based on structure–activity relationships (SAR), some additional activities are also predicted, which point towards new possible applications of these lipids. This review is devoted to synthetic lipids ferrocenes and titanocenes steroid conjugates and their biological activity, which are of great interest for medicine, as well as for pharmacologists and the pharmaceutical industry.