Role of the C(6)-hydroxy group in bicyclomycin: synthesis, structure, and chemical, biochemical, and biological properties

Journal of Medicinal Chemistry
A SantillánH Kohn

Abstract

Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the transcription termination factor rho. A recent structure-activity relationship study of 1 showed that replacing the C(6)-hydroxy group with alkoxy and thioalkoxy substituents led to dramatic losses of inhibitory activity in rho biochemical assays. The origin for this structural specificity has been explored by the synthesis and chemical, biochemical, and biological evaluation of C(6)-amino- (13), C(6)-(hydroxylamino)-(14), and C(6)-mercaptobicyclomycin (15). These compounds, like 1, are capable of entering into hydrogen bond donor interactions with rho and are capable of undergoing C(6) ring opening to generate alpha, beta-unsaturated carbonyl, imine, or thione systems. The chemical reactivity of 13-15 was compared with that of 1. We observed that 1, upon treatment with EtSH under moderate and basic conditions, readily underwent C(6) hemiaminal bond cleavage followed by conjugate addition to beta-methylene-alpha-ketoamide 2 to give Michael addition adducts whereas 13-15 reacted by initial cleavage of the C(1)-O(2) bond. Biochemical and biological assays of 13-15 and related analogues demonstrated that the C(6) hydroxy group in 1 ...Continue Reading

References

Oct 1, 1972·The Journal of Antibiotics·T MiyoshiH Sakai
Sep 1, 1973·The Journal of Antibiotics·S MiyamuraH Tanaka
Sep 15, 1988·Physical Review A: General Physics·A D Becke

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Citations

Sep 28, 2005·Bioorganic & Medicinal Chemistry·Boon-Saeng ParkHarold Kohn
Jul 4, 2003·The Journal of Organic Chemistry·Andrew P BroganHarold Kohn

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