A new synthesis of alkene-containing minor-groove binders and essential hydrogen bonding in binding to DNA and in antibacterial activity.
A practical synthesis of alkene-containing minor-groove binders for DNA, related to distamycin, with potential for wide structural diversity is described, based upon the Wittig chemistry of N-alkylpyrrole aldehydes. The compounds prepared have been evaluated for binding to DNA by physical methods (melting temperature and NMR) and for their antibacterial activity. Significantly, it was found that alkenes linking the aryl head group of the minor-groove binder promote strong binding to DNA and high antibacterial activity against Gram-positive bacteria. Conversely, a minor-groove binder containing an alkene located towards the alkylamino tail group has a low affinity for DNA and does not show antibacterial activity. These observations suggest an important role for specific hydrogen bonds in the binding of compounds of this type to DNA, and in their antibacterial activity.
Anthony
Nahoum G
NG
Strathclyde Institute of Pharmacy and Biomedical Sciences, The John Arbuthnott Building, 27 Taylor Street, Glasgow, G4 0NR, Scotland.
Breen
David
D
Donoghue
Gavin
G
Khalaf
Abedawn I
AI
Mackay
Simon P
SP
Parkinson
John A
JA
Suckling
Colin J
CJ
D000475:Alkenes / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013210:Staphylococcus / Q000187:drug effects
D000475:Alkenes; D000900:Anti-Bacterial Agents; D004247:DNA