title: Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents.
abstract: Polycyclic aromatic hydrocarbons are widespread in nature with a toxicity range from non-toxic to extremely toxic. A series of pyrenyl derivatives has been synthesized following a four-step strategy where the pyrene nucleus is attached with a basic heterocyclic moiety through a carbon linker. Virtual screening of the physicochemical properties and druggability has been carried out. The cytotoxicity of the compounds (1-8) have been evaluated in vitro against a small panel of human cancer cell lines which includes two liver cancer (HepG2 and Hepa 1-6), two colon cancer (HT-29 and Caco-2) and one each for cervical (HeLa) and breast (MCF-7) cancer cell lines. The IC50 data indicate that compound 6 and 8 are the most effective cytotoxic agents in the present set of pyrenyl derivatives, suggesting that having a 4-carbon linker is more effective than a 5-carbon linker and the presence of amide carbonyl groups in the linker severely reduces the efficacy of the compound. The compounds showed selectivity toward cancer cells at lower doses (<5 μM) when compared with the normal hepatocytes. The mechanism of action supports the cell death through apoptosis in a caspase-independent manner without cleavage of poly (ADP-ribose) polymerase (PARP), even though the compounds cause plasma membrane morphological changes. The compounds, whether highly cytotoxic or mildly cytotoxic, localize to the membrane of cells. The compounds with either a piperidine ring (6) or an N-methyl piperazine (8) in the side chain were both capable of circumventing the drug resistance in SKOV3-MDR1-M6/6 ovarian cancer cells overexpressing P-glycoprotein. Qualitative structure-activity relationship has also been studied.
authors.affiliation: Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA.
authors.forename: Debasish
authors.initials: D
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA; University of Texas Health Science Center at San Antonio-Regional Academic Health Center, Medical Research Division, 1214 West Schunior Street, Edinburg, TX 78541, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Sanchez
authors.affiliation: Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Guerrero
authors.affiliation: University of Texas Health Science Center at San Antonio-Regional Academic Health Center, Medical Research Division, 1214 West Schunior Street, Edinburg, TX 78541, USA.
authors.forename: Fang-Mei
authors.initials: FM
authors.lastname: Chang
authors.affiliation: University of Texas Health Science Center at San Antonio-Regional Academic Health Center, Medical Research Division, 1214 West Schunior Street, Edinburg, TX 78541, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Granados
authors.affiliation: University of Texas Health Science Center at San Antonio-Regional Academic Health Center, Medical Research Division, 1214 West Schunior Street, Edinburg, TX 78541, USA; Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: shortj@uthscsa.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Short
authors.affiliation: Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg, TX 78539, USA. Electronic address: banik@utpa.edu.
authors.forename: Bimal K
authors.initials: BK
authors.lastname: Banik
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D011721:Pyrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011721:Pyrenes
keywords: Anticancer; Apoptosis; Cytotoxicity; Drug resistance; PAH; Polycyclic; Pyrene