Synthesis and biological activity of amino acid derivatives of avarone and its model compound

• Published in: Bioorganic & medicinal chemistry 2015-11, Vol.23 (21), p.6930-6942
• Main Authors: Vilipić, Jovana, Novaković, Irena, Stanojković, Tatjana, Matić, Ivana, Šegan, Dejan, Kljajić, Zoran, Sladić, Dušan
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial activity; Apoptosis; Apoptosis - drug effects; Avarone; Caspase; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cyclohexenes - chemical synthesis; Cyclohexenes - chemistry; Cyclohexenes - toxicity; Cytotoxicity; Drug Screening Assays, Antitumor; Fungi - drug effects; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; HeLa Cells; Humans; K562 Cells; Microbial Sensitivity Tests; Quinones - chemical synthesis; Quinones - chemistry; Quinones - toxicity; Sesquiterpenes - chemical synthesis; Sesquiterpenes - chemistry; Sesquiterpenes - toxicity; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.09.044

[Display omitted] A series of eighteen derivatives of marine sesquiterpene quinone avarone and its model system tert-butylquinone with amino acids has been synthesized by nucleophilic addition of amino acids to the quinones. In vitro cytotoxic activity toward human cancer cell lines (HeLa, A549, Fem-X, K562, MDA-MB-453) and normal MRC-5 cell line was determined. Several compounds showed very strong inhibitory activity with IC50 values less than 10μM. Avarone derivatives were more active than the corresponding tert-butylquinone derivatives. The results of the cytofluorimetric analysis of cell cycle of HeLa cells showed that apoptosis might be one of possible mechanism of action of these compounds in cancer cells. In order to examine the influence of caspases on cell death, the apoptotic mechanisms induced by the tested compounds were determined using specific caspases 3, 8 and 9 inhibitors. For all compounds antibacterial activities against six strains of Gram-positive and four strains of Gram-negative bacteria were determined, as well as antifungal activity against three fungal species.