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Eur J Med Chem. 2015 Oct 20;103:226-37. doi: 10.1016/j.ejmech.2015.08.047. Epub 2015 Aug 29.

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

Author information

1
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
2
Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
3
Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, Amiens, France.
4
Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377 Munich, Germany.
5
Department of Chemistry, New Mexico Tech, 801 Leroy Place, Socorro, NM 87801, USA; Department of Biology, New Mexico Tech, 801 Leroy Place, Socorro, NM 87801, USA.
6
Center of Innovation and Preclinical Studies, Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, Brazil; Department of Pharmacology, UFSC, Florianópolis SC 88.056-000, Brazil.
7
Department of Comprehensive Dentistry, Cancer Therapy and Research Center, UTHSCSA, San Antonio, TX 78229, USA.
8
Department of Pharmacology, UTHSCSA, San Antonio, TX 78229, USA.
9
Department of Biomedical Sciences, University of Illinois, College of Medicine, 1601 Parkview Ave, Rockford, IL 61107, USA.
10
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126 Napoli, Italy.
11
Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Outeiro de São João Batista, s/n° Campus do Valonguinho, Centro-Niterói, RJ 24020-140, Brazil.
12
Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
13
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA. Electronic address: a_k76@txstate.edu.

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.

KEYWORDS:

Cannabidiol; Capsaicin; Glioblastoma; Ion channel; Resiniferatoxin; Vanilloid

PMID:
26360047
PMCID:
PMC4617783
DOI:
10.1016/j.ejmech.2015.08.047
[Indexed for MEDLINE]
Free PMC Article

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