Microwave Synthesis and Evaluation of Phenacylhomoserine Lactones as Anticancer Compounds that Minimally Activate Quorum Sensing Pathways in Pseudomonas aeruginosa

Journal of Medicinal Chemistry
2009.0

Abstract

The bacterial quorum sensing (QS) signal molecule 3-oxo-dodecanoyl-L-homoserine lactone (OdDHL) is produced by the opportunistic pathogen Pseudomonas aeruginosa and controls expression of virulence factors associated with life threatening infections in immune compromised individuals. OdDHL has also demonstrated anticancer activity, yet its ability to enhance pathogenicity of P. aeruginosa compromises further consideration as a potential anticancer agent. In search of acylhomoserine lactones that selectively inhibit cancer cell growth, a library of phenacylhomoserine lactone analogues has been prepared by microwave synthesis and evaluated for cancer growth inhibition and quorum sensing activation. Comparative SAR analysis demonstrates that both anticancer and QS signaling systems require long acyl side chains with a 3-oxo substitution for maximum activity. Compound 12b, 3-oxo-12-phenyldodecanoyl-L-homoserine lactone, was identified as a lead compound with strong cancer growth inhibitory activity that minimizes activation of QS signaling pathways in a P. aeruginosa reporter assay.

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