Giovanni Ughetto

Interactions of Quinoxaline Antibiotic and DNA.: The Molecular Structure of a Triostin A—d(GCGTACGC) Complex

The crystal structure of a DNA octamer d(GCGTACGC) complexed to an antitumor antibiotic, triostin A, has been solved and refined to 2.2 A resolution by x-ray diffraction analysis. The antibiotic molecule acts as a true bis intercalator surrounding the d(CpG) sequence at either end of the unwound right-handed DNA double helix. As previously observed in the structure of triostin A-d(CGTACG) complex (A.H.-J. Wang, et. al., Science, 225, 1115-1121 (1984)), the alanine amino acid residues of the drug molecule form sequence-specific hydrogen bonds to guanines in the minor groove. The two central A.T base pairs are in Hoogsteen configuration with adenine in the syn conformation. In addition, the two terminal G.C base pairs flanking the quinoxaline rings are also held together by Hoogsteen base pairing. This is the first observation in an oligonucleotide of. Hoogsteen G.C base pairs where the cytosine is protonated. The principal functional components of a bis-intercalative compound are discussed.

Structure of 11-deoxydaunomycin bound to DNA containing a phosphorothioate.

The anthracyclines form an important family of cancer chemotherapeutic agents with a strong dependence of clinical properties on minor differences in chemical structure. We describe the X-ray crystallographic solution of the three-dimensional structure of the anthracycline 11-deoxydaunomycin plus d(CGTsACG). In this complex, two drug molecules bind to each hexamer duplex. Both the drug and the DNA are covalently modified in this complex in contrast with the three previously reported DNA-anthracycline complexes. In the 11-deoxydaunomycin complex the 11 hydroxyl group is absent and a phosphate oxygen at the TpA step has been replaced by a sulfur atom leading to a phosphorothioate with absolute stereochemistry R. Surprisingly, removal of a hydroxyl group from the 11 position does not alter the relative orientation of the intercalated chromophore. However, it appears that the phosphorothioate modification influenced the crystallization and caused the 11-deoxydaunomycin-d(CGTsACG) complex to crystallize into a different lattice (space group P2) with different lattice contacts and packing forces than the non-phosphorothioated DNA-anthracycline complexes (space group P4(1)2(1)2). In the minor groove of the DNA, the unexpected position of the amino-sugar of 11-deoxydaunomycin supports the hypothesis that in solution the position of the amino sugar is dynamic.