The role of carboxymethyl substituents in the interaction of tetracationic porphyrins with DNA.
Cationic porphyrin-based compounds capable of interacting with DNA are currently under extensive investigation as prospective anticancer and anti-infective drugs. One of the approaches to enhancing the DNA-binding affinity of these ligands is chemical modification of functional groups of the porphyrin macrocycle. We analyzed the interaction with DNA of novel derivatives containing carboxymethyl and ethoxycarbonylmethyl substituents at quaternary nitrogen atoms of pyridinium groups at the periphery of the porphyrin macrocycle. The parameters of binding of 5,10,15,20-tetrakis(N-carboxymethyl-4-pyridinium)porphyrin (P1) and 5,10,15,20-tetrakis(N-ethoxycarbonylmethyl-4-pyridinium)porphyrin (P2) to double-stranded DNA sequences of different nucleotide content were determined using optical spectroscopy. The association constant of P1 interaction with calf thymus DNA (K = 3.4 × 10(6) M(-1)) was greater than that of P2 (K = 2.8 × 10(5) M(-1)). Preferential binding of P1 to GC- rather than AT-rich oligonucleotides was detected. In contrast, P2 showed no preference for particular nucleotide content. Modes of binding of P1 and P2 to GC and AT duplexes were verified using the induced circular dichroism spectra. Molecular modeling confirmed an intercalative mode of interaction of P1 and P2 with CpG islands. The carboxyl groups of the peripheral substituent in P1 determine the specific interactions with GC-rich DNA regions, whereas ethoxycarbonylmethyl substituents disfavor binding to DNA. This study contributes to the understanding of the impact of peripheral substituents on the DNA-binding affinity of cationic porphyrins, which is important for the design of DNA-targeting drugs.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Oxana A
OA
Kovaleva
Vladimir B
VB
Tsvetkov
Anna K
AK
Shchyolkina
Olga F
OF
Borisova
Valentina A
VA
Ol'shevskaya
Anton V
AV
Makarenkov
Alexander S
AS
Semeikin
Alexander A
AA
Shtil
Dmitry N
DN
Kaluzhny
D004247:DNA / Q000737:chemistry*; D062105:Molecular Docking Simulation; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry*; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*
D011166:Porphyrins; D011726:Pyridinium Compounds; D004247:DNA; C427203:calf thymus DNA