Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents
| Autor: | Jorge L. Sanchez, Jose C. Granados, Adrian M. Guerrero, Bimal K. Banik, Debasish Bandyopadhyay, Fang Mei Chang, Johnny D Short |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
Cell Survival Druggability Antineoplastic Agents Apoptosis HeLa chemistry.chemical_compound Structure-Activity Relationship Amide Drug Discovery Tumor Cells Cultured Moiety Humans Cytotoxicity Cell Proliferation Pharmacology Pyrenes biology Molecular Structure Chemistry Organic Chemistry Dose-Response Relationship Radiation General Medicine Hep G2 Cells biology.organism_classification Drug Design Cancer cell MCF-7 Cells Pyrene Caco-2 Cells Drug Screening Assays Antitumor Linker HT29 Cells HeLa Cells |
| Zdroj: | European journal of medicinal chemistry. 89 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect