Abstract
The syntheses of C-13 epimeric 3-[(1-benzyl-1,2,3-triazol-4-yl)methoxy]-d-secoestrones are reported. Triazoles were prepared from 3-(prop-2-inyloxy)-d-secoalcohols and p-substituted benzyl azides via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The antiproliferative activities of the products and their precursors were determined in vitro against a panel of human adherent cervical (HeLa, SiHa and C33A), breast (MCF-7, MDA-MB-231, MDA-MB-361 and T47D) and ovarian (A2780) cell lines by means of MTT assays. The orientation of the angular methyl group and the substitution pattern of the benzyl group of the azide greatly influenced the cell growth-inhibitory potential of the compounds. The 13β derivatives generally proved to be more potent than their 13α counterparts. Introduction of a benzyltriazolylmethyl group onto the 3-OH position seemed to be advantageous. One 13α compound containing an unsubstituted benzyltriazolyl function displayed outstanding antiproliferative activities against three cell lines.
Highlights
Anticancer drug design based on synthetic modifications of naturally occurring biomolecules may lead to nontoxic drug candidates with selective antitumoral potencies [1,2]
Novel antiproliferative triazolyl D-secoestrone derivatives were synthesized by introducing the triazolylmethyl linker between the 3-OH and the benzyl or p-substituted benzyl protecting group
The “clicking” of benzyl azides to the 3-propargyl-D-secoestrones led to potent antiproliferative compounds
Summary
Anticancer drug design based on synthetic modifications of naturally occurring biomolecules may lead to nontoxic drug candidates with selective antitumoral potencies [1,2]. Estrone-based anticancer agents are already utilized in therapy, but one of the most important requirements of these drugs is a lack of original hormonal activity [3,4]. We recently reported that 3-benzyl ethers of D-secoestrone alcohol or oxime (compounds 1 and 2, Figure 1.) exert substantial in vitro cell growth-inhibitory action against a number of cancer cell lines, with IC50 values in the low micromolar or submicromolar range [10,11]. It was concluded that the nature of the 3- and 17-functional groups exerts a great impact on the antiproliferative behavior of the compounds. Derivatives containing a 17-oxime function displayed more pronounced cytostatic properties than those of 17-hydroxymethyl derivatives. 3-Hydroxy-D-secooxime 2, but not the D-secoalcohol 1, was further derivatized by introducing a terminal alkyne function onto the 3-OH
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