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Journal of Radioanalytical and Nuclear Chemistry

, Volume 298, Issue 2, pp 1149–1157 | Cite as

Synthesis of selectively deuterated and tritiated lupane derivatives with cytotoxic activity

  • Martin Vlk
  • Milan Urban
  • Tomas Elbert
  • Jan SarekEmail author
Article

Abstract

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 14), 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 1014, 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 (68, 11, 14, 18, 19, 21, 22, 24 and 25) have not been reported before.

Keywords

Isotopic labelling Tritium Deuterium Betulin Betulinic acid Cytotoxicity 

Notes

Acknowledgments

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.

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Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2013

Authors and Affiliations

  • Martin Vlk
    • 1
  • Milan Urban
    • 2
  • Tomas Elbert
    • 3
  • Jan Sarek
    • 2
    Email author
  1. 1.Faculty of Nuclear Sciences and Physical EngineeringCzech Technical University in PraguePrague 1Czech Republic
  2. 2.Department of Organic Chemistry, Faculty of Science, Institute of Molecular and Translational MedicinePalacky UniversityOlomoucCzech Republic
  3. 3.Laboratory of Radioisotopes, Institute of Organic Chemistry and BiochemistryAcademy of SciencesPrague 6Czech Republic

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