Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents

Debasish Bandyopadhyay, Jorge L. Sanchez, Adrian M. Guerrero, Fang Mei Chang, Jose C. Granados, John D. Short, Bimal K. Banik

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 (<51/4M) 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.

Original languageEnglish (US)
Pages (from-to)851-862
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume89
DOIs
StatePublished - Jan 7 2015

Keywords

  • Anticancer
  • Apoptosis
  • Cytotoxicity
  • Drug resistance
  • PAH
  • Polycyclic
  • Pyrene

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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