Synthesis and Biological Evaluation of Triazolyl 13α-Estrone-Nucleoside Bioconjugates.
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).
Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. bodnar.brigitta@med.u-szeged.hu.
Brigitta
B
Bodnár
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. bobe@chem.u-szeged.hu.
Erzsébet
E
Mernyák
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. wolfling@chem.u-szeged.hu.
János
J
Wölfling
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. schneider@chem.u-szeged.hu.
Gyula
G
Schneider
1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary. herman.bius@gmail.com.
Bianka Edina
BE
Herman
1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary. szecsi.mihaly@med.u-szeged.hu.
Mihály
M
Szécsi
Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary. sinkaiza@gmail.com.
Izabella
I
Sinka
Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary. zupko@pharm.u-szeged.hu.
István
I
Zupkó
Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. kupihar.zoltan@med.u-szeged.hu.
Zoltán
Z
Kupihár
Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. kovacs.lajos@med.u-szeged.hu.
Lajos
L
Kovács
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009705:Nucleosides; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
13α-estrone; 17β-HSD1; antiproliferative; copper-catalyzed alkyne–azide click reaction; nucleosides; triazoles