SYNTHESIS OF 2 DISTAMYCIN ANALOGS AND THEIR BINDING MODE TO D(CGCAAATTTGCG)(2) IN THE 2 1 SOLUTION COMPLEXES AS DETERMINED BY 2-DIMENSIONALH-1-NMR/

In the course of a study aimed at the synthesis of pyrrole amidine car boxamide DNA-binding agents as novel pharmacological agents, a series of carbamoyl analogues of distamycin, containing an increasing number of pyrrole units, have been obtained by total synthesis. The interacti on of the tetrapyrrole carbamoyl 4 with the dodecamer d(CGCAAATTTGCG)( 2) in comparison with that of the corresponding formylamino analogue 3 has been examined by high-resolution H-1-NMR and molecular modeling. Either ligand binds to DNA in one-drug and symmetric two-drug modes at low drug:DNA ratios, while at high ratios only the two-drug complex w as observed. In this article, the structure of 2:1 drugs DNA complexes has been studied by NMR and molecular modeling, which indicate that t he two analogues bind the DNA in a similar fashion, in the minor groov e of the 5'-AATTT region. In both complexes the two drugs are symmetri cally placed along the complementary strands of DNA with the pyrrole r ing of one molecule in close contact with those of the other one. Alth ough another region of five consecutive A-T base pairs is available, n o evidence of sliding of drug molecules between different binding site s, as in the case of the 2:1 complex of distamycin with the same dodec amer, is observed, thus indicating that increasing the number of N-met hylpyrrolecarboxamide units from three to four cases a lengthening of the recognition sequence.