Stereocontrolled synthesis of the four possible 3-methoxy and 3-benzyloxy-16-triazolyl-methyl-estra-17-ol hybrids and their antiproliferative activities

Abstract

The four possible isomers of each of 3-methoxy-and 3-benzyloxyestra-1,3,5(10)trien-17-ols (5-8 and 9-12) were converted through 16-p-tosyloxymethyl-or 16-bromomethyl derivatives into their 3-methoxy-and 3-benzyloxy-16-azidomethylestra(1,3,5(10)-triene derivatives (13-16 and 17-20). The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of these compounds with different terminal alkynes afforded novel 1,4-disubstituted diastereomers (21a-f, 22a-f, 23a-f, 24a-f and 25a-f, 26a-f, 27a-f, 28a-f). The antiproliferative activities of the structurally related triazoles were determined in vitro with the microculture tetrazolium assay on four malignant human cell lines of gynecological origin (Hela, SiHa, MCF-7 and MDA-MB-231).

Antiproliferative and Antimetastatic Properties of 16-Azidomethyl Substituted 3-O-Benzyl Estrone Analogs

“…Our current study has focused on investigating the antiproliferative properties of four 16-azidomethyl estradiol analogs ( 1 – 4 ) previously utilized as intermediaries in synthesizing 16-triazolyl estranes [ 17 ]. Our screens for antiproliferative activity were extended to cover two estrone congeners ( 16AABE and 16BABE ), and compounds with a 17-keto function were found to be more active than the reference agent cisplatin.…”

“…n.d.: not determined. *: data are from refererence [ 17 ]. Numeric results with calculated IC 50 values are presented in Supplementary Table S1 .…”

“…We have recently reported on certain 16,17-functionalized 3-methoxy or 3-benzyloxy estrone derivatives behaving as potent antiproliferative compounds [ 16 , 17 ]. The substitution pattern of ring D, and the nature of the protecting group at C-3- O was demonstrated to influence the cell growth-inhibitory potential of these compounds markedly.…”

“…Overall, 3-benzyl ethers were found to be more potent [ 16 ]. The substituents’ nature and orientation affected the antitumoral behavior of these previously tested agents [ 17 ].…”