Synthesis andin vitropharmacological evaluation ofN-[(1-benzyl-1,2,3-triazol-4-yl)methyl]-carboxamides ond-secoestrone scaffolds

Abstract

An efficient synthesis of several N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]carboxamides in the 13b-and 13a-D-secoestrone series is reported. Novel triazoles were synthesized via the Cu(I)-catalyzed azide-alkyne cycloaddition of steroidal alkynyl carboxamides and p-substituted benzyl azides. Each of the products was evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431 and A2780). Some of them exhibited activities similar to those of the reference agent cisplatin. On change of the substitution pattern of the benzyl group of the azide, great differences in the cell growth-inhibitory properties were observed. The p-alkylbenzyl-substituted triazoles selectively exerted high cytostatic action against A2780 cells, with IC 50 values of 1 mM. We investigated the potential inhibitory action exerted on the human 17b-HSD1 activity of the new secosteroids. Three triazoles effectively suppressed the estrone to 17b-estradiol conversion with IC 50 values in low micromolar range.

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

“…Accordingly, the 13α-estrane core may serve as fundamental moiety for the design of hormonally inactive estrone derivatives bearing promising biological activities. We recently published the syntheses and the in vitro biological evaluations of several 13α-estrone derivatives [6–9]. Certain compounds proved to be biologically active, bearing substantial antiproliferative or enzyme inhibitory potential [7–8].…”

Structural analysis and biomedical potential of novel salicyloyloxy estrane derivatives synthesized by microwave irradiation

“…Inhibitory effects exerted on steroidogenic enzymes by the newly synthesized compounds 7, 10-12 and 14 were investigated with in vitro radio-labeled substrate incubations (Table 1). Our previously published methods for 3bHSD [28,34,35], 17bHSD1 [7], 17bHSD2 [27,28] and 17bHSD3 [28] were used with minor modifications. During procedures, tissue preparations serving as enzyme sources were incubated with 1 lM [ 14 C]-labeled substrate steroids in the presence of 0.1 mM coenzymes at 37°C.…”

“…17b-Hydroxysteroid dehydrogenase type 1 (17bHSD1) activates the less active estrone to 17bestradiol, a potent ligand for estrogen receptors; thus, inhibitors of this enzyme are highly interesting potential therapeutic agents for the control of estrogen-dependent diseases such as endometriosis, as well as breast and ovarian cancers. 17bHSD1 is inhibited by some estradiol derivatives [4][5][6][7]. 17bHSD2 catalyzes the reverse process (17b-estradiol to estrone); thus, inhibitors of this isoform could enable better regulation of the levels of active estrogens.…”

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

“…Human placental cytosol served as a source for the isozyme 21,23 . Human term placenta specimens were combined and homogenized with an Ultra-Turrax in 0.1 M HEPES buffer (pH ¼ 7.3) containing 1 mM EDTA and 1 mM dithiotreitol and the cytosol was obtained by fractionated centrifugation.…”

“…We recently described the synthesis and in vitro investigation of the 17b-HSD1-inhibitory activities of C-13 epimeric 17-(triazolylmethyl)carboxamido D-secoestrone derivatives bearing ether protecting groups on C-3 21 . The nature of the functional groups on C-3 and/or C-17 and the orientation of the angular methyl group influence the enzyme inhibitory potential substantially.…”