Theoretical design, chemical synthesis and footprinting analysis of a novel peptide derivative of the intercalator 7-H pyridocarbazole targeted towards the major groove of DNA.
In order to target the major groove of DNA, we have designed novel peptide derivatives of 7-H pyridocarbazole, which is the chromophoric ring of ditercalinium, a potent antitumor bisintercalator. We will present here the results obtained with a compound that has a D-Asn tethered to the pyridinium nitrogen of the ring by a protonated beta-alanyl-ethyl chain. We have investigated two alternative means of intercalation of the chromophore: first, into the (pyrpur) sequences, d(CpG)2 and d(CpA).d(TpG); second, into the (pur-pyr) sequences, d(GpC)2 and d(GpT).d(ApC). For the first intercalative mode, the best bound triplet sequences are d(ACG).d(CGT) and d(ACA)d(TGT), namely with an adenine immediately upstream from the intercalation site. In these complexes, the chromophore has its concave side in the major groove, its long axis nearly colinear with the mean long axis of the two base pairs of the intercalation site, and a bidentate H-bonded configuration occurs which involves the C = O and NH groups of the D-Asn side chain and HN6 and N7 (resp.) of the adenine base upstream. One alkylammonium proton is H-bonded to N7 of the guanine of the intercalation site, on the strand opposite to the one bearing the adenine. In the second intercalative mode, the chromophore's concave site now faces one DNA strand, and both alkylammonium protons are involved in H-bonds with N7 and O6 of the 3' guanine on the same strand. The peptide's complexes with sequences having A, G, or C upstream of this guanine were computed to be energetically competitive with those with the best (pyr-pur) triplets. This provides a rare example of energetically favourable drug intercalation in-between (pur-pyr) sequences as compared to the standard (pyr-pur) ones. The synthesis of this compound was performed, and a series of footprinting experiments undertaken on a total of approximately 300 nucleotides. These experiments were consistent with the inferences from the theoretical computations.
Laboratoire de Biochimie Théorique, Institut de Biologie-Physico-Chimique, Paris, France.
N
N
Gresh
B
B
René
X W
XW
Hui
M C
MC
Barsi
B P
BP
Roques
C
C
Garbay
D001483:Base Sequence; D002227:Carbazoles / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010449:Peptide Mapping; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D012091:Repetitive Sequences, Nucleic Acid
D002227:Carbazoles; D007364:Intercalating Agents; D010455:Peptides; C092016:10-methoxy-7H-pyrido(4,3-c)carbazole; D004247:DNA