Molecular structure of antitumor drug steffimycin and modelling of its binding to dna

The molecular and crystal structure of steffimycin have been determined by single crystal X- ray diffraction to 0.9 Ǻ resolution. The triclinic crystals are in the space group P1, with the unit cell dimensions of a = 8.606(3) Ǻ, b=22.168(7) Ǻ, c=8.448(2) Ǻ, a=97.56(3)°, β=95.97(2)°, γ=87.94(3)°, Z=2. The structure was solved by direct methods and refined by the full-matrix least-squares method to a final R value of 0.065 with 3405 (I_net> 2.0 o(I_net)) observed reflections using the NRCVAX software package. The crystal lattice includes 2 independent steffimycin, 3 water and one 2-methyl-2, 4-pentanediol molecules. The conformation of steffimycin is grossly similar to other anthracycline antibiotics including daunorubicin. The crystal packing interactions of steffimycin suggest a preferred stacking of the aglycone chromophore of the antibiotic which resembles the intercalative interactions seen in the daunorubicin-d(CGTACG) (Wang et al., Biochemistry 26, 1152 (1987)) and nogalamycin-d(CGT(pS)ACG) (Liaw et al. Biochemistry 28, 9913 (1989)) complexes. The atomic coordinates data from these complexes were used to model the intercalative binding of steffimycin to DNA. The models were then stereochemically idealized by the constraint refinement program NUCLSQ. Subsequently XPLOR software package was used for energy minimization of these models in vacuo. The model building studies suggest that steffimycin has a higher CpG base sequence specificity over the TpA step, similar to that of daunorubicin and nogalamycin.