Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

Ramesh Dasari, Annelise De Carvalho, Derek C. Medellin, Kelsey N. Middleton, Frédéric Hague, Marie N.M. Volmar, Liliya V. Frolova, Mateus F. Rossato, Jorge J. De La Chapa, Nicholas F. Dybdal-Hargreaves, Akshita Pillai, Roland E. Kälin, Véronique Mathieu, Snezna Rogelj, Cara B. Gonzales, João B. Calixto, Antonio Evidente, Mathieu Gautier, Gnanasekar Munirathinam, Rainer GlassPatricia Burth, Stephen C. Pelly, Willem A.L. Van Otterlo, Robert Kiss, Alexander Kornienko

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation.

Original languageEnglish (US)
Article number8083
Pages (from-to)226-237
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume103
DOIs
StatePublished - Oct 20 2015

Keywords

  • Glioblastoma Ion channel Capsaicin Vanilloid Resiniferatoxin Cannabidiol

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Dasari, R., De Carvalho, A., Medellin, D. C., Middleton, K. N., Hague, F., Volmar, M. N. M., Frolova, L. V., Rossato, M. F., De La Chapa, J. J., Dybdal-Hargreaves, N. F., Pillai, A., Kälin, R. E., Mathieu, V., Rogelj, S., Gonzales, C. B., Calixto, J. B., Evidente, A., Gautier, M., Munirathinam, G., ... Kornienko, A. (2015). Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines. European Journal of Medicinal Chemistry, 103, 226-237. [8083]. https://doi.org/10.1016/j.ejmech.2015.08.047