Structural, conformational, and theoretical binding studies of antitumor antibiotic porfiromycin (N-methylmitomycin C), a covalent binder of DNA, by X-ray, NMR, and molecular mechanics.
X-ray, NMR, and molecular mechanics studies on antitumor antibiotic porfiromycin (C16H20N4O5), a covalent binder of DNA, have been carried out to study the structure, conformation, and theoretical interactions with DNA. The crystal structure was solved by direct methods and refined to an R value of 0.052. The configurations at C(9), C(9a), C(1), and C(2) are S, R, S, and S, except for the orientation of the aziridine ring and (carbamoyloxy)methyl side chain. The five-membered ring attached to the aziridine ring adopts an envelope conformation. The solution conformation is similar to that observed in the solid state except for the (carbamoyloxy)methyl side chain. Monovalent and cross-linked models of the drug bound to DNA have been energetically refined by using molecular mechanics. The results indicate that, in the case of monocovalent binding, the drug clearly prefers a d(CpG) sequence rather than a d(GpC) sequence. In the case of the cross-linked model there is no clear-cut preference of d(CpG) over d(GpC), indicating that the binding preference of the drug may be kinetic rather than thermodynamic.
Arora
S K
SK
Department of Crystallography, University of Pittsburgh, Pennsylvania 15260.
Cox
M B
MB
Arjunan
P
P
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011160:Porfiromycin / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014961:X-Ray Diffraction
D000903:Antibiotics, Antineoplastic; D004247:DNA; D011160:Porfiromycin