Oliver Colin M, Schaefer Amy L, Greenberg E Peter, Sufrin Janice R
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
J Med Chem. 2009 Mar 26;52(6):1569-75. doi: 10.1021/jm8015377.
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.
细菌群体感应（QS）信号分子3-氧代-十二烷酰-L-高丝氨酸内酯（OdDHL）由机会致病菌铜绿假单胞菌产生，并控制与免疫功能低下个体中危及生命的感染相关的毒力因子的表达。OdDHL也已证明具有抗癌活性，但其增强铜绿假单胞菌致病性的能力妨碍了其作为潜在抗癌剂的进一步研究。为了寻找选择性抑制癌细胞生长的酰基高丝氨酸内酯，通过微波合成制备了一系列苯甲酰高丝氨酸内酯类似物，并对其进行了癌细胞生长抑制和群体感应激活评估。比较性的构效关系分析表明，抗癌和QS信号系统都需要具有3-氧代取代的长酰基侧链才能达到最大活性。化合物12b，即3-氧代-12-苯基十二烷酰-L-高丝氨酸内酯，被鉴定为一种先导化合物，具有很强的癌细胞生长抑制活性，在铜绿假单胞菌报告基因检测中能将QS信号通路的激活降至最低。
