Fluorine-substituted dihydrobicyclomycins: synthesis and biochemical and biological properties.
Many studies show that selective introduction of fluorine within pharmacological agents leads to improved activities. In this study, we determine the effects of aryl fluorine substitution in 5a-(benzylsulfanyl)-dihydrobicyclomycin (3) on the in vitro inhibition of Escherichia coli rho-dependent ATPase activity. Compound 3 is an analog of bicyclomycin (1), which is the only known selective inhibitor of rho, and 1 and 3 have comparable in vitro inhibitory activities. We demonstrate that aryl fluorine substitution of 3 leads to increase in inhibitory activity but that the beneficial effects due to fluorine were dependent upon the site and number of fluorine substituents. The bioactivities are rationalized in terms of the bond moment created by the aryl fluoride bond within the 5a-aryl dihydrobicyclomycin-rho-binding pocket. Use of this hypothesis led to the design of dihydrobicyclomycin derivatives with superior in vitro rho inhibitory activities.
Park
Boon-Saeng
BS
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
Widger
William
W
Kohn
Harold
H
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005461:Fluorine; C096667:dihydrobicyclomycin