Diacridines: bifunctional intercalators. I. Chemistry, physical chemistry and growth inhibitory properties.
The synthesis, as well as the rationale for synthesis of diacridines, double intercalators, as potential inhibitors of nucleic acid synthesis is presented. The syntheses of (9-acridyl)-putrescine and -spermine, and bis(-9-acridyl)-putrescine, -spermidine, -spermine diamines and of bis(6-chloro-2-methoxy-9-acridyl)-putrescine and -spermine diamines, all substituted on the terminal NH2 groups are described. In addition, the homologous series of diacridines connected by the amino groups of the diamines NH2(CH2)nNH2 (where n = 2,3,4,6,8,10,12,14,16,18) to the C-9 of the diacridines has been synthesized. The chemical properties of these compounds as well as their molecular relationship to DNA are presented. The effect of the double intercalators on the Tm of DNA and of (A)n - (U)n, (dA)n - (dT)n, (G)n - (C)n and on (dG)n - (dC)n have been determined. The double acridine intercalators produce a much greater increase of the Tm of these nucleic acids than do the single acridine intercalators. They also profoundly affect the Tm of DNA in physiological salt concentrations; under these latter conditions the single intercalators have no effect. The relationship between the length of the chain connecting the two acridine rings and the inhibition of the growth of P-388 cells in vitro and vivo is presented. Their growth inhibitory properties appear, in general, to parallel their intercalative abilities.
D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D002951:Citrates; D004247:DNA / Q000096:biosynthesis; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009994:Osmolar Concentration; D011119:Polynucleotides / Q000096:biosynthesis; D013096:Spermine; D013329:Structure-Activity Relationship; D013696:Temperature
D000166:Acridines; D002951:Citrates; D011119:Polynucleotides; D013096:Spermine; D004247:DNA