Stereoselective synthesis of optically active bicyclic beta-lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria.
Optically active bicyclic beta-lactams were synthesized, starting from 2-H-delta 2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the beta-lactam framework were investigated. A rapid CsOH saponification of the beta-lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic beta-lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-delta 2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic beta-lactam carboxylic acids 7a-g and aldehydes 4a-d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. beta-Lactams substituted with large acyl substitutents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic beta-lactams constitute a new class of potential bacterial chaperone inhibitors.
Emtenäs
Hans
H
Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Carlsson
Marcus
M
Pinkner
Jerome S
JS
Hultgren
Scott J
SJ
Almqvist
Fredrik
F
D001419:Bacteria / Q000472:pathogenicity*; D002264:Carboxylic Acids / Q000737:chemistry*; D010861:Fimbriae, Bacterial / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D047090:beta-Lactams / Q000737:chemistry*
D002264:Carboxylic Acids; D047090:beta-Lactams