The solution conformation of the antibiotic anticancer chromomycin A3 by two-dimensional NMR spectroscopy.
The solution conformations of chromomycin A3 (CRA) and dechromose-A chromomycin A3 (CRA-B) in dichloromethane and methanol were studied by two-dimensional (2D) NMR techniques. In dichloromethane, the drugs are found in a compact wedged-like conformation, with the phenolic hydroxyls at the tip and the side chains folded back to one side of the aglycon plane, oriented parallel to each other. The overall structure is stabilised by intramolecular hydrogen bonds and by the formation of a hydrophobic pocket, enclosed by the three side chains. In methanol, the drugs have the expected open conformation with extended side chains. Like its parent drug, CRA-B binds to d(ATGCAT)2 duplex with a major groove orientation, a 2:1 drug/duplex ratio and a two-fold symmetry of the resultant complex. The drug molecule is suggested to reside diagonally across the two strands of the duplex and to span 3 base pairs, while all three side chains of the drug are folded away from the major groove of the DNA. The observed nonequivalent positions of CRA and CRA-B within the major groove of the duplex results from the different conformation adopted by the sugar side-chains in the two complexes.
Berman
E
E
Organic Chemistry Department, Weizmann Institute of Science, Rehovot, Israel.
Kam
M
M
D014128:Chromomycin A3 / Q000031:analogs & derivatives / Q000378:metabolism; D002865:Chromomycins / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol; D008752:Methylene Chloride; D008958:Models, Molecular; D008968:Molecular Conformation; D012996:Solutions
D002865:Chromomycins; D012996:Solutions; C059745:dechromose-A chrommycin A3; D008752:Methylene Chloride; D004247:DNA; D014128:Chromomycin A3; D000432:Methanol