Interaction between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG)

The crystal structure of a morpholino derivative of adriamycin bound to DNA hexamer d(CGTACG) has been determined at 1.5 Amstrong resolution. The complex crystallizes in space group P1 with unit cell dimensions a = 18.01 Amstrong, b = 18.83 Amstrong, c = 27.65 Amstrong, alpha = 92.6°, beta = 100.5°, gamma = 94.9° and there are two drug molecules bound per duplex. Morpholino derivatives differ greatly from their parent compounds in their biological and pharmacological properties. Structural comparison of this complex with the series of previously reported anthracycline-DNA complexes offers an opportunity for studying relationships between structure and function. The anthracycline cromophore intercalates at the CpG step and DNA distortion from a B-type conformation are similar to those observed in other DNA-anthracycline complexes. Interactions between drug and DNA show no difference at the intercalation site, while in the minor groove they are significantly affected by the presence of the bulky morpholinyl moiety on the anthracycline amino sugar. The binding site involves four base pairs and the absence of a positive charge on the amino sugar appears to influence the hydratation pattern on both grooves. The two halves of the duplex are symmetrically related by non-crystallographic 2-fold axis but they are not equivalent. In one half, one magnesium cluster bridges both drug and DNA, further stabilizing the complex.