Rational design of substituted tripyrrole peptides that complex with DNA by both selective minor-groove binding and electrostatic interaction with the phosphate backbone.
The structures of the compounds we call 3a, 3b, and 3c-compounds that incorporate (i) the tripyrrole peptide of the minor-groove-binding distamycin class of compounds and (ii) polyamine ligands that extend from the minor groove and can interact with phosphodiester bonds--were arrived at by computer-graphics designing by using the x-ray structure of distamycin A complexed in the minor groove of d(CGCAAATTTGCG)2. Compounds 3a, 3b, and 3c are elaborations of distamycin analog 2, designed for improved stability in solution and easier synthesis and purification, which itself binds weakly to DNA. Compounds 3a, 3b, and 3c have been synthesized, and the interaction of distamycin A, 2, 3a, 3b, and 3c with calf thymus DNA, poly(dA-dT), poly(dG-dC), poly(dI-dC), pBR322 superhelical plasmid DNA, and, in the case of 3b, T4 coliphage DNA have been studied. The following pertinent conclusions can be drawn. Binding of 3a, 3b, and 3c occurs in the minor groove of DNA and, because of favorable electrostatic interaction of diprotonated polyamine side chains and DNA phosphodiester linkages, the tenacity of DNA binding and site specificity of 3a, 3b, and 3c are comparable to that of native distamycin A. 3b has been found to induce changes in the superhelical density of pBR322 plasmid DNA. The study establishes that the central pyrrole N-CH3 substituent of 2 can be replaced by bulky polyamine metal ligands to create any number of compounds that bind into the minor groove at A + T-rich sites and are putative catalysts for the hydrolysis of DNA.
Bruice
T C
TC
Department of Chemistry, University of California, Santa Barbara 93106.
Mei
H Y
HY
He
G X
GX
Lopez
V
V
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D003461:Crystallography; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004278:DNA, Superhelical / Q000737:chemistry; D004214:Distamycins / Q000737:chemistry; D015195:Drug Design; D006868:Hydrolysis; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids; D011758:Pyrroles / Q000737:chemistry*
D004278:DNA, Superhelical; D004214:Distamycins; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D011758:Pyrroles; C030000:stallimycin; D004247:DNA