Abstract
Figure Presented. 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 β-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)-N 3-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3348-3359 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 54 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 12 2011 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
Cite this
Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone. / Jadhav, Gopal; Chhabra, Siri Ram; Telford, Gary; Hooi, Doreen S.W.; Righetti, Karima; Williams, Paul; Kellam, Barrie; Pritchard, David I.; Fischer, Peter M.
In: Journal of Medicinal Chemistry, Vol. 54, No. 9, 12.05.2011, p. 3348-3359.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Immunosuppressive but non-LasR-inducing analogues of the pseudomonas aeruginosa quorum-sensing molecule N-(3-Oxododecanoyl)-l-homoserine Lactone
AU - Jadhav, Gopal
AU - Chhabra, Siri Ram
AU - Telford, Gary
AU - Hooi, Doreen S.W.
AU - Righetti, Karima
AU - Williams, Paul
AU - Kellam, Barrie
AU - Pritchard, David I.
AU - Fischer, Peter M.
PY - 2011/5/12
Y1 - 2011/5/12
N2 - Figure Presented. 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 β-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)-N 3-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.
AB - Figure Presented. 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 β-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)-N 3-octylmalonamide (25d) to be over twice as potent as 1 as an immune suppressor while displaying LasR-induction antagonist activity.
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U2 - 10.1021/jm2001019
DO - 10.1021/jm2001019
M3 - Article
VL - 54
SP - 3348
EP - 3359
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -