Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity

0398914 - ÚOCHB 2014 RIV HU eng J - Journal Article
Vlk, M. - Urban, M. - Elbert, Tomáš - Šarek, J.
Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity.
Journal of Radioanalytical and Nuclear Chemistry. Roč. 298, č. 2 (2013), s. 1149-1157. ISSN 0236-5731. E-ISSN 1588-2780
Grant - others:GA ČR(CZ) GA305/09/1216
Institutional support: RVO:61388963
Keywords : isotopic labelling * tritium * deuterium * betulin * betulinic acid * cytotoxicity
Subject RIV: CB - Analytical Chemistry, Separation
Impact factor: 1.415, year: 2013

The aim of this work was to synthesize deuterated and tritiated analogues of highly oxidized lupane derivatives known from our group. We selected compounds that previously showed very high cytotoxic activity on multiple cancer cell lines in order to further investigate the mechanism of their action. From starting material (compounds 1-4), we obtained benzyl platanate (5) and its reaction with deuteromethyltriphenylphosphonium iodide gave deuterated compound 6. Following benzyl deprotection gave free acid 7 and oxidation with SeO2 gave 30-oxo-[29-H-2(2)]lup-20(29)-en-28-oic acid (8), which is one of the most active compounds synthesized in our group to date (IC50 6 mu mol/L on CEM cell line). The alkylation of benzyl 2-hydroxy-3-oxolupa-1,20(29)-dien-28-oate (9) with methyliodide or deuteromethyliodide followed by a series of deprotection and hydrogenation steps gave compounds 10-14, where 2 beta-[31-H-2(3)]methoxy-3-oxolupan-20(29)-en-28-oic acid (13) is especially interesting, it showed lower activity on CEM cell line (IC50 10 mu mol/L) however, it was very active against Ph1-positive human leukemia BV-173 (IC50 0.91 mu mol/L) and against human myelogenous leukemia K562 (IC50 0.52 mu mol/L). Selectively labelled [3 alpha-H-2] and [3 alpha-H-3] methyl 3 beta-acetoxy-21,22-dioxolup-18-en-28-oates 24, 25 were prepared in three steps by reduction of corresponding 3-oxo derivatives and they showed moderate activity on CEM cell line (IC50 10 mu mol/L). In total, 11 labelled compounds (6-8, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.
Permanent Link: http://hdl.handle.net/11104/0226393