Immunosuppressive but Non-LasR-Inducing Analogues of the Pseudomonas aeruginosa Quorum-Sensing Molecule N-(3-Oxododecanoyl)-l-homoserine Lactone

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• 作者：Gopal P. Jadhav ; Siri Ram Chhabra ; Gary Telford ; Doreen S. W. Hooi ; Karima Righetti ; Paul Williams ; Barrie Kellam ; David I. Pritchard ; Peter M. Fischer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 12, 2011
• 年：2011
• 卷：54
• 期：9
• 页码：3348-3359
• 全文大小：989K
• 年卷期：v.54,no.9(May 12, 2011)
• ISSN：1520-4804

文摘

The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (1) is involved not only in bacterial activation but also in subversion of the host immune system, and this compound might thus be used as a template to design immunosuppressive agents, provided derivatives devoid of quorum-sensing activity could be discovered. By use of a leukocyte proliferation assay and a newly developed bioluminescent P. aeruginosa reporter assay, systematic modification of 1 allowed us to delineate the bacterial LasR-induction and host immunosuppressive activities. The main determinant is replacement of the methylene group proximal to the 尾-ketoamide in the acyl chain of 1 with functions containing heteroatoms, especially an NH group. This modification can be combined with replacement of the homoserine lactone system in 1 with stable cyclic groups. For example, we found the simple compound N¹-(5-chloro-2-hydroxyphenyl)-N³-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.