Synthetic Analogues of the Bacterial Signal (Quorum Sensing) Molecule N-(3-oxododecanoyl)-L-homoserine Lactone as Immune Modulators

J Med Chem. 2003 Jan 2;46(1):97-104. doi: 10.1021/jm020909n.

Abstract

Comparative immune modulatory activity for a range of synthetic analogues of a Pseudomonas aeruginosa signal molecule, N-(3-oxododecanoyl)-l-homoserine lactone (3O, C(12)-HSL), is described. Twenty-four single or combination systematic alterations of the structural components of 3O, C(12)-HSL were introduced as described. Given the already defined immunological profile of the parent compound, 3O, C(12)-HSL, these compounds were assayed for their ability to inhibit murine and human leucocyte proliferation and TNF-alpha secretion by lipopolysaccharide (LPS) stimulated human leucocytes in order to provide an initial structure-activity profile. From IC(50) values obtained with a murine splenocyte proliferation assay, it is apparent that acylated l-homoserine lactones with an 11-13 C side chain containing either a 3-oxo or a 3-hydroxy group are optimal structures for immune suppressive activity. These derivatives of 3O, C(12)-HSL with monounsaturation and/or a terminal nonpolar substituent on the side chain were also potent immune suppressive agents. However, structures lacking the homoserine lactone ring, structures lacking the l-configuration at the chiral center, and those with polar substituents were essentially devoid of activity. The ability of compounds selected from the optimal activity range to modulate mitogen-driven human peripheral blood mononuclear cell proliferation and LPS-induced TNF-alpha secretion indicates the suitability of these compounds for further investigation in relation to their molecular mechanisms of action in TNF-alpha driven immunological diseases, particularly autoimmune diseases such as psoriasis, rheumatoid arthritis, and type 1 (autoimmune) diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis*
  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Cell Division / drug effects
  • Homoserine / analogs & derivatives*
  • Homoserine / chemical synthesis*
  • Homoserine / chemistry
  • Homoserine / pharmacology
  • Humans
  • In Vitro Techniques
  • Lactones / chemical synthesis*
  • Lactones / chemistry
  • Lactones / pharmacology
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Neutrophil Activation
  • Pseudomonas aeruginosa*
  • Spleen / cytology
  • Spleen / drug effects
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adjuvants, Immunologic
  • Lactones
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Pseudomonas aeruginosa autoinducer
  • Homoserine