The interaction with DNA of unfused aromatic systems containing terminal piperazino substituents. Intercalation and groove-binding.
A number of unfused tricyclic aromatic intercalators have shown excellent activity as amplifiers of the anticancer activity of the bleomycins and the 4',6-diphenylpyrimidines, 2a and 2b, with terminal basic functions (4-methylpiperazino groups) have been synthesized to test the structural requirements for amplifier-DNA interactions. The terminal piperazine rings are bulky, have limited flexibility, and are twisted out of the phenyl ring plane in both 2a and 2b. With 2a the pyrimidine is unsubstituted at position 5 and the conformation predicted by molecular mechanics calculations has a 25-30 degrees twist between the phenyl and pyrimidine ring planes. With 2b the 5-position is substituted with a methyl group and this causes a larger twist angle (50-60 degrees) between the phenyl and pyrimidine planes. These conformational variations lead to markedly different DNA interactions for 2a and 2b. Absorption, CD and NMR spectral, viscometric, flow dichroism and kinetics results indicate that 2a binds strongly to DNA by intercalation while 2b binds more weakly in a groove complex. The general structure and conformation of 2a, a slightly twisted, unfused-aromatic system with terminal piperazino groups is more similar to groove-binding agents such as Hoechst 33258 than to intercalators. The fact that 2a forms a strong intercalation complex with DNA is unusual but in agreement with studies on other amplifiers of anticancer drug action. Molecular modeling studies provide a second unusual feature of the 2a intercalation complex. While most well-characterized intercalators bind with their bulky and/or cationic substitutents in the DNA minor groove, the cationic piperazino groups of 2a are too large to bind in the minor groove in an intercalation complex but can form strong interactions with DNA in the major groove. The tricyclic aromatic ring system of 2a stacks well with adjacent base-pairs in the major-groove complex and the piperazino groups have good electrostatic and van der Waals interactions with the DNA backbone.
Wilson
W D
WD
Department of Chemistry, Georgia State University, Atlanta 30303.
Barton
H J
HJ
Tanious
F A
FA
Kong
S B
SB
Strekowski
L
L
D000818:Animals; D002021:Buffers; D002417:Cattle; D004247:DNA / Q000032:analysis*; D007364:Intercalating Agents / Q000032:analysis*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010879:Piperazines / Q000032:analysis*; D013055:Spectrophotometry, Infrared; D014783:Viscosity
D002021:Buffers; D007364:Intercalating Agents; D010879:Piperazines; D004247:DNA