Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity
- 276 Downloads
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-[29-2H2]lup-20(29)-en-28-oic acid (8), which is one of the most active compounds synthesized in our group to date (IC50 6 μmol/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 2β-[31-2H3]methoxy-3-oxolupan-20(29)-en-28-oic acid (13) is especially interesting, it showed lower activity on CEM cell line (IC50 10 μmol/L) however, it was very active against Ph1—positive human leukemia BV-173 (IC50 0.91 μmol/L) and against human myelogenous leukemia K562 (IC50 0.52 μmol/L). Selectively labelled [3α-2H] and [3α-3H] methyl 3β-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 μmol/L). In total, 11 labelled compounds (6–8, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.
KeywordsIsotopic labelling Tritium Deuterium Betulin Betulinic acid Cytotoxicity
This study was supported partially by the Czech Science Foundation (305/09/1216), MSM 6840770040 and SGS 10/212/OHK4/2T/14. We are grateful to Bohunka Šperlichová for measuring the optical rotatory power and Professor Jiří Klinot and Miloš Buděšínský for help with interpretation of NMR data. Special thanks to Drs. Kesner and Pasztor (NICOLET CZ) for special services in IR instrumentation. Many thanks also to Associate Professor Ladislav Lešetický.
- 5.Pokrovskii AG, Shintyapina AB, Pronkina NV, Kozhevnikov VS, Plyasunova OA, Shults EE, Tolstikov GA (2006) Biochem Biophys Mol Biol 407:94Google Scholar
- 6.Sarek J, Kvasnica M, Vlk M, Biedermann D (2010) In: Salvador JAR (ed) Pentacyclic triterpenes as promising agents in cancer, 1st edn. Nova Science Publishers, New YorkGoogle Scholar
- 7.Sarek J, Kvasnica M, Vlk M, Urban M, Dzubak P, Hajduch M (2011) In: Murph M (ed) Research on melanoma: a glimpse into current directions and future trends, 1st edn. Intech, RijekaGoogle Scholar
- 8.Hajduch M, Sarek J (2001) Triterpenoid derivatives. PCT Int. Patent Appl. WO0190136Google Scholar
- 9.Hajduch M, Sarek J (2001) Triterpenoid derivatives. PCT Int. Patent Appl. WO0190046Google Scholar
- 10.Hajduch M, Sarek J (2001) Triterpenoid derivatives. PCT Int. Patent Appl. WO0190096Google Scholar
- 14.Sarek J, Hajduch M, Svoboda M (2008) Method of preparation and isolation of betulin diacetate from birch bark from paper mills and its optional processing to betulin. Patent CZ 301038Google Scholar
- 16.Krasutsky PA, Puschenikov A, Sergeeva T (2006) Selective oxidation of triterpenes employing TEMPO. WO2006105354Google Scholar
- 18.Urban M, Klinot J, Tislerova I, Biedermann D, Hajduch M, Cisarova I, Sarek J (2006) Synthesis 23:3979Google Scholar