Abstract
2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC). For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3′-hydroxy groups of the nucleosides were protected by acetyl groups and the 5′-hydroxy groups were modified by the tosyl–azide exchange method. The commonly used conditions for click reaction between the protected-5′-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I) catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780) and the potential inhibitory activity of the new conjugates on human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 μM). The thymidine conjugate displayed considerable 17β-HSD1 inhibitory activity (IC50 = 19 μM).
Highlights
Estrogens are synthesized biochemically in a multistep process from cholesterol in human body [1], and are responsible for the development of secondary sexual characteristics in females and maintenance of central nervous system, cardiovascular system and bones
For the preparation of 50 -azido-20,50 -dideoxynucleosides, first we have followed the tosyl–azide replacement method based on the literature but the isolated yields were significantly lower in our hands (Scheme 1, path a) compared to those described in the literature [35,36,37,38,39] we decided to protect the 30 -hydroxy groups (Scheme 1, path b)
As a commonly used 3% trichloroacetic acid/dichloromethane deprotection resulted in a considerable amount of depurination side-products we have changed the reagent to a deprotection mixture containing the Lewis acid boron trifluoride in a
Summary
Estrogens are synthesized biochemically in a multistep process from cholesterol in human body [1], and are responsible for the development of secondary sexual characteristics in females and maintenance of central nervous system, cardiovascular system and bones. Since they play a crucial role in the cell proliferation, overproduction of estrogens may lead to enhanced proliferation of hormone sensitive cells, resulting in hormone dependent cancers: ovarian, uterine, breast, prostate and endometrial [2]. It catalyzes the reduction of estrone to 17β-estradiol, which enhances enhances the the proliferation proliferation of of certain certain cancer cancer cells cells [4]
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