New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships

Jan Šarek, Jiří Klinot, Petr Džubák, Eva Klinotová, Věra Nosková, Václav Křeček, Gabriela Kořínková, Jean Oliver Thomson, Anna Janošťáková, Shudong Wang, Simon Parsons, Peter M. Fischer, Nikolai Zhelev, Marián Hajdúch

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Abstract

Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure−activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure−activity relationship.
Original languageEnglish
Pages (from-to)5402–5415
Number of pages14
JournalJournal of Medicinal Chemistry
Volume46
Issue number25
DOIs
StatePublished - 2003

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Structure-Activity Relationship
Neoplasms
Pentacyclic Triterpenes
Tumor Cell Line
Ketones
Oxygen
Acids
In Vitro Techniques

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Šarek, J., Klinot, J., Džubák, P., Klinotová, E., Nosková, V., Křeček, V., ... Hajdúch, M. (2003). New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships. Journal of Medicinal Chemistry, 46(25), 5402–5415. DOI: 10.1021/jm020854p

Šarek, Jan; Klinot, Jiří; Džubák, Petr; Klinotová, Eva; Nosková, Věra; Křeček, Václav; Kořínková, Gabriela; Thomson, Jean Oliver; Janošťáková, Anna; Wang, Shudong; Parsons, Simon; Fischer, Peter M.; Zhelev, Nikolai; Hajdúch, Marián / New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships.

In: Journal of Medicinal Chemistry, Vol. 46, No. 25, 2003, p. 5402–5415.

Research output: Contribution to journalArticle

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author = "Jan Šarek and Jiří Klinot and Petr Džubák and Eva Klinotová and Věra Nosková and Václav Křeček and Gabriela Kořínková and Thomson, {Jean Oliver} and Anna Janošťáková and Shudong Wang and Simon Parsons and Fischer, {Peter M.} and Nikolai Zhelev and Marián Hajdúch",
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Šarek, J, Klinot, J, Džubák, P, Klinotová, E, Nosková, V, Křeček, V, Kořínková, G, Thomson, JO, Janošťáková, A, Wang, S, Parsons, S, Fischer, PM, Zhelev, N & Hajdúch, M 2003, 'New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships' Journal of Medicinal Chemistry, vol 46, no. 25, pp. 5402–5415. DOI: 10.1021/jm020854p

New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships. / Šarek, Jan; Klinot, Jiří; Džubák, Petr; Klinotová, Eva; Nosková, Věra; Křeček, Václav; Kořínková, Gabriela; Thomson, Jean Oliver; Janošťáková, Anna; Wang, Shudong; Parsons, Simon; Fischer, Peter M.; Zhelev, Nikolai; Hajdúch, Marián.

In: Journal of Medicinal Chemistry, Vol. 46, No. 25, 2003, p. 5402–5415.

Research output: Contribution to journalArticle

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AU - Šarek,Jan

AU - Klinot,Jiří

AU - Džubák,Petr

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AU - Nosková,Věra

AU - Křeček,Václav

AU - Kořínková,Gabriela

AU - Thomson,Jean Oliver

AU - Janošťáková,Anna

AU - Wang,Shudong

AU - Parsons,Simon

AU - Fischer,Peter M.

AU - Zhelev,Nikolai

AU - Hajdúch,Marián

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AB - Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure−activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure−activity relationship.

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Šarek J, Klinot J, Džubák P, Klinotová E, Nosková V, Křeček V et al. New lupane derived compounds with pro-apoptotic activity in cancer cells: synthesis and structure−activity relationships. Journal of Medicinal Chemistry. 2003;46(25):5402–5415. Available from, DOI: 10.1021/jm020854p