Joint molecular modeling and spectroscopic studies of DNA complexes of a bis(arginyl) conjugate of a tricationic porphyrin designed to target the major groove.
To target selectively the major groove of double-stranded B DNA, we have designed and synthesized a bis(arginyl) conjugate of a tricationic porphyrin (BAP). Its binding energies with a series of double-stranded dodecanucleotides, having in common a central d(CpG)2 intercalation site were compared. The theoretical results indicated a significant energy preference favoring major groove over minor groove binding and a preferential binding to a sequence encompassing the palindrome GGCGCC encountered in the Primary Binding Site of the HIV-1 retrovirus. Spectroscopic studies were carried out on the complexes of BAP with poly(dG-dC) and poly(dA-dT) and a series of oligonucleotide duplexes having either a GGCGCC, CCCGGG, or TACGTA sequence. The results of UV-visible and circular dichroism spectroscopies indicated that intercalation of the porphyrin takes place in poly(dG-dC) and all the oligonucleotides. Thermal denaturation studies showed that BAP increased significantly the melting temperature of the oligonucleotides having the GGCGCC sequence, whereas it produced only a negligible stabilization of sequences having CCCGGG or TACGTA in place of GGCGCC. This indicates a preferential binding of BAP to GGCGCC, fully consistent with the theoretical predictions. IR spectroscopy on d(GGCGCC)2 indicated that the guanine absorption bands, C6=O6 and N7-C8-H, were shifted by the binding of BAP, indicative of the interactions of the arginine arms in the major groove. Thus, the de novo designed compound BAP constitutes one of the very rare intercalators which, similar to the antitumor drugs mitoxantrone and ditercalinium, binds DNA in the major groove rather than in the minor groove.
Mohammadi
S
S
Laboratoire de Chimie Structurale et Spectroscopie Biomoléculaire (CNRS-URA 1430), Université Paris 13, Bobigny, France.
Perrée-Fauvet
M
M
Gresh
N
N
Hillairet
K
K
Taillandier
E
E
D001120:Arginine / Q000737:chemistry*; D001665:Binding Sites; D002412:Cations; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D046911:Macromolecular Substances; D008958:Models, Molecular; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry*; D011489:Protein Denaturation; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature
D002412:Cations; D046911:Macromolecular Substances; D011166:Porphyrins; C092399:meso-tetrakis(1-methyl-4-pyridiniumyl)porphyrin; D004247:DNA; D001120:Arginine