Synthesis of Two Distamycin Analogs and Their Binding Mode to d(CGCAAATTTGCG)2 in the 2:1 Solution Complexes as Determined by Two-Dimensional 1H-NMR (original) (raw)
1995, Journal of Medicinal Chemistry
I n the course of a study aimed a t the synthesis of pyrrole amidine carboxamide DNA-binding agents as novel pharmacological agents, a series of carbamoyl analogues of distamycin, containing a n increasing number of pyrrole units, have been obtained by total synthesis. The interaction of the tetrapyrrole carbamoyl 4 with the dodecamer d (C G C M W G C G) 2 in comparison with that of the corresponding formylamino analogue 3 has been examined by highresolution lH-NMR and molecular modeling. Either ligand binds to DNA in one-drug and symmetric two-drug modes a t low drug:DNA ratios, while at high ratios only the two-drug complex was observed. In this article, the structure of 2:l drugs DNA complexes has been studied by NMR and molecular modeling, which indicate that the two analogues bind the DNA in a similar fashion, in the minor groove of the B '-A A W region. In both complexes the two drugs are symmetrically placed along the complementary strands of DNA with the pyrrole ring of one molecule in close contact with those of the other one. Although another region of five consecutive AT base pairs is available, no evidence of sliding of drug molecules between different binding sites, as in the case of the 2:l complex of distamycin with the same dodecamer, is observed, thus indicating that increasing the number of N-methylpyrrolecarboxamide units from three to four cases a lengthening of the recognition sequence.
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