Synthesis and in Vitro Antiproliferative Evaluation of C-13 Epimers of Triazolyl-d-Secoestrone Alcohols: The First Potent 13α-d-Secoestrone Derivative

Abstract

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.

Mechanism of antiproliferative action of a new d -secoestrone-triazole derivative in cervical cancer cells and its effect on cancer cell motility

“…Among these analogs, a compound with a 3-triazole substituent (D-SET) was found to the most effective on cervical carcinoma cell lines, while it has no significant inhibitory effect on the non-cancerous human fetal lung fibroblast (MRC-5) cells. We also reported that the antiproliferative effectivity and tumor selectivity of D-SET is more potent than that of cisplatin [61], a drug regularly used in cervical tumor therapy [32]. In view of these data, we performed other steroid analogs such as the natural steroid alkaloid solanidine, the natural estrogen metabolite 2-ME or the synthetic D-homoestrone [12,55,57].…”

“…In view of the previously mentioned most active secoalcohol, new analogs have been designed and proliferation-inhibitory effects have been detected. As expected, the derivatives with triazole substituents demonstrated the most pronounced anticancer effect on several malignant tumor cell lines tested [32].…”

“…Our previous studies demonstrated that D-ring modification in the estrogen structure can cause a potent antiproliferative effect in vitro [20,32,57,60]; we also reported about the considerable antitumor effects of several D-secoestrone derivatives in eight different reproductive cancer cell lines [32]. Among these analogs, a compound with a 3-triazole substituent (D-SET) was found to the most effective on cervical carcinoma cell lines, while it has no significant inhibitory effect on the non-cancerous human fetal lung fibroblast (MRC-5) cells.…”

“…show that D-SET exerts a pronounced growth-inhibitory effect on HeLa cells with a 1.12 μM IC50 value and on C-33 A cells with a 1.77 μM IC50 value, but it has no substantial inhibitory potential on SiHa or MRC-5 (IC50 > 30 μM) [32] after 72 h.…”

“…Experiments were carried out in the same way as described previously [32]. Briefly, cells were plated into 96-well plates at a density of 5,000 cells/well in the cases of HeLa and SiHa, and 10,000 cells/well in the case of C-33 A, and incubated with increasing concentrations of D-SET (0.1-30.0 μM) under cell-culturing conditions.…”