Mernyák Erzsébet, Kovács Ida, Minorics Renáta, Sere Péter, Czégány Dóra, Sinka Izabella, Wölfling János, Schneider Gyula, Újfaludi Zsuzsanna, Boros Imre, Ocsovszki Imre, Varga Mónika, Zupkó István
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
J Steroid Biochem Mol Biol. 2015 Jun;150:123-34. doi: 10.1016/j.jsbmb.2015.04.001. Epub 2015 Apr 3.
Novel 16-triazoles in the 13α-estrone series were synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition of the two diastereomeric (on C-16 and on C-17) 16-azido-13α-estra-1,3,5(10)-trien-17-ol 3-benzyl ethers with substituted phenylacetylenes. The new heterocyclic derivatives were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431, A2780, T47D, MDA-MB-231 and MDA-MB-361). The inversion of the configurations at C-16 and C-17 selectively affected the growth-inhibitory properties of the tested compounds. The 16β,17α isomers generally proved to be potent on all cell lines, with IC50 values comparable to those of the reference agent cisplatin. Change of the substitution pattern of the phenyl group of the acetylene led to great differences in antiproliferative properties. Exclusively the p-phenyl-substituted triazoles exerted high cytostatic effects. One of the most potent compounds activated caspase-3 and caspase-9 without influencing caspase-8, confirming the induction of apoptosis via the intrinsic pathway.
通过铜（I）催化的两种非对映异构体（在C-16和C-17上）的16-叠氮基-13α-雌甾-1,3,5（10）-三烯-17-醇3-苄基醚与取代苯乙炔的叠氮化物-炔烃环加成反应，合成了13α-雌酮系列中的新型1,2,3-三唑。通过MTT法对新型杂环衍生物进行体外评估，以检测其对一组人贴壁癌细胞系（HeLa、MCF-7、A431、A2780、T47D、MDA-MB-231和MDA-MB-361）的抗增殖活性。C-16和C-17构型的翻转选择性地影响了测试化合物的生长抑制特性。16β,17α异构体通常在所有细胞系上都具有活性，其IC50值与参考药物顺铂相当。乙炔基苯基取代模式的改变导致抗增殖特性存在很大差异。只有对苯基取代的三唑具有高细胞抑制作用。最有效的化合物之一激活了caspase-3和caspase-9，而不影响caspase-8，证实了通过内源性途径诱导细胞凋亡。
