Design, synthesis, and biological evaluation of platensimycin analogues with varying degrees of molecular complexity.
The molecular design, chemical synthesis, and biological evaluation of two distinct series of platensimycin analogues with varying degrees of complexity are described. The first series of compounds probes the biological importance of the benzoic acid subunit of the molecule, while the second series explores the tetracyclic cage domain. The biological data obtained reveal that, while the substituted benzoic acid domain of platensimycin is a highly conserved structural motif within the active compounds with strict functional group requirements, the cage domain of the molecule can tolerate considerable structural modifications without losing biological action. These findings refine our present understanding of the platensimycin pharmacophore and establish certain structure-activity relationships from which the next generation of designed analogues of this new antibiotic may emerge.
Nicolaou
K C
KC
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
Stepan
Antonia F
AF
Lister
Troy
T
Li
Ang
A
Montero
Ana
A
Tria
G Scott
GS
Turner
Craig I
CI
Tang
Yefeng
Y
Wang
Jianhua
J
Denton
Ross M
RM
Edmonds
David J
DJ
D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062365:Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001547:Benzaldehydes / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052117:Benzodioxoles / Q000737:chemistry; D053138:Cyclohexenes / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D062365:Aminobenzoates; D000813:Anilides; D000814:Aniline Compounds; D000890:Anti-Infective Agents; D001547:Benzaldehydes; D001565:Benzoates; D052117:Benzodioxoles; D053138:Cyclohexenes; D004852:Epoxy Compounds; D011714:Pyrans; C005454:piperonal; D000218:Adamantane; C510909:platensimycin
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