A Crystallographic and Spectroscopic Study of the Complex between d(CGCGAATTCGCG)₂ and 2,5-Bis(4-guanylphenyl)furan, an Analogue of Berenil. Structural Origins of Enhanced DNA-Binding Affinity

Abstract

2,5-Bis(4-guanylphenyl)furan ("furamidine") is a dicationic minor groove binding drug that has been shown to be more effective than pentamidine against the Pneumocystis carinii pathogen in an immunosuppressed rat model. It has a close structural similarity to the antitrypanosomal drug berenil, differing only on the replacement of the central triazene unit with a furan moiety. we have determined the crystal structure of the complex between furamidine and the DNA dodecamer d(CGCGAATTCGCG)2 and compared it with the same DNA sequence by UV-visible, fluorescence, and CD spectroscopy. Furamidine shows tighter binding to this sequence (Keq = 6.7 x 10(6)) than berenil (Keq = 6.6 x 10(5)). The crystal structure reveals that, unlike berenil, furamidine makes direct hydrogen bond interactions with this DNA sequence through both amidinium groups to O2 atoms of thymine bases and is more isohelical with the minor groove. Molecular mechanics calculations support the hypothesis that these differences result in the improved interaction energy between the ligand and the DNA.

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

“…Interestingly, all of the linear compounds give induced CD signals with the -AATT-sequence that are smaller than for classically curved minor groove binding compounds such as DB75. 59 This has been observed previously with other linear minor groove binding agents 12,14 and appears to be a characteristic of such compounds with AT sequences. The strong positive induced CD signals with DB1242 and -GCTCG-show that the weak CD signals are not characteristic of all sequences and are in agreement with the impressive binding of DB1242 with the -GCTCG-sequence as observed by other methods.…”

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

“…3 It was one of the first heterocyclic diamidines studied in detail and the compound was crystallized as a minor groove complex with the DNA duplex dodecamer sequence d(CGCGAATTCGCG) 2 . 4 In this complex, DB75 forms cross strand H-bonds with thymine keto groups at the floor of the groove and generally fits to the shape of the groove at the AATT site in the self-complementary duplex. The complex structure is similar to that for netropsin bound to the same DNA sequence 5 but netropsin forms more H-bonds and the binding is enthalpy driven, contrasting with the entropy driven binding for DB75.…”

Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: uma introdução

“…De fato, foi observado que em tal conformação iso-hélica, deve ocorrer possível interação com os pares de bases nitrogenadas do DNA 54 , descrita também nas estruturas cristalográficas [55][56][57][58][59] . Os ligantes na fenda menor interagem preferencialmente com os pares de base AT (adenina e timina), pois a guanina possui um substituinte, que é uma amina aromática, voltada para o interior da fenda menor, causando impedimento estereoquímico.…”