title: Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Dasari
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Annelise
authors.initials: A
authors.lastname: De Carvalho
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Medellin
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Middleton
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hague
authors.affiliation: Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377 Munich, Germany.
authors.forename: Marie N M
authors.initials: MN
authors.lastname: Volmar
authors.affiliation: 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.
authors.forename: Liliya V
authors.initials: LV
authors.lastname: Frolova
authors.affiliation: 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.
authors.forename: Mateus F
authors.initials: MF
authors.lastname: Rossato
authors.affiliation: Department of Comprehensive Dentistry, Cancer Therapy and Research Center, UTHSCSA, San Antonio, TX 78229, USA.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: De La Chapa
authors.affiliation: Department of Pharmacology, UTHSCSA, San Antonio, TX 78229, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dybdal-Hargreaves
authors.affiliation: Department of Biomedical Sciences, University of Illinois, College of Medicine, 1601 Parkview Ave, Rockford, IL 61107, USA.
authors.forename: Akshita
authors.initials: A
authors.lastname: Pillai
authors.affiliation: Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377 Munich, Germany.
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kälin
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.affiliation: 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.
authors.forename: Snezna
authors.initials: S
authors.lastname: Rogelj
authors.affiliation: Department of Comprehensive Dentistry, Cancer Therapy and Research Center, UTHSCSA, San Antonio, TX 78229, USA.
authors.forename: Cara B
authors.initials: CB
authors.lastname: Gonzales
authors.affiliation: 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.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126 Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gautier
authors.affiliation: Department of Biomedical Sciences, University of Illinois, College of Medicine, 1601 Parkview Ave, Rockford, IL 61107, USA.
authors.forename: Gnanasekar
authors.initials: G
authors.lastname: Munirathinam
authors.affiliation: Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377 Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Burth
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pelly
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA. Electronic address: a_k76@txstate.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornienko
mesh_terms: D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D028502:Polygonum / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D054697:Cytostatic Agents; D011758:Pyrroles; D012717:Sesquiterpenes; C034380:polygodial
keywords: Cannabidiol; Capsaicin; Glioblastoma; Ion channel; Resiniferatoxin; Vanilloid