Synthesis, conformation, and interaction with DNA of unfused heteropolyaromatic molecules substituted with cationic side chains

Thesis/Dissertation · Wed Jan 01 04:00:00 EST 1992

OSTI ID:7265389

Harden, Jr, D B

Pyrimidines containing aryl or heteroaryl substituents in the 4 and/or 6 positions and a cationic side chain in the 2 position have been shown to interact with DNA by intercalation. A novel and efficient synthesis of 2-chloro-4-heteroarylpyrimidines and 2-chloro-4,6-di(heteroaryl)pyrimidines is presented. The addition of organo-lithium reagent to 2-chloropyrimidine produces 2-chloro-4-heteroaryl-3,4-dihydropyrimidines, which are quantitatively aromatized with DDQ to yield 2-chloro-4-heteroarylpyrimidines. A second addition of organo-lithium reagents, followed by oxidation with DDQ produces 2-chloro-4,6-di(heteroaryl)pyrimidines. Substitution of the chlorine atom by nucleophiles containing a cationic tether produces unfused bicyclic and tricyclic DNA intercalators. These pyrimidines have also been shown to amplify the degradation of DNA by the anticancer drug bleomycin (BLM). Computer aided molecular mechanics studies of putrescine (66), spermidine (67), and spermine (68) binding to the B-DNA decamer (dGdC)[sub 5][center dot](dGdC)[sub 5] causes a bend of the helical axis towards the major groove and a significant widening of the minor groove. These polyamines amplify BLM-mediated degradation of DNA in the same order. A mechanism for the amplification of BLM-mediated degradation of DNA by DNA intercalating pyrimidines is proposed. In this mechanism the pyrimidines interact with DNA by intercalation from the DNA major groove, which induces a better stereochemical binding site for BLM in the minor groove. Pyrimidines with an amino linkage to the side chain have lower DNA binding constants than their corresponding thioether analogues. Low temperature [sub 1]H NMR investigations of selected DNA binding pyrimidines suggest that conformations of the cationic side chains contribute to the DNA binding characteristics of these compounds.

• Research Organization: Georgia State Univ., Atlanta, GA (United States)
• OSTI ID: 7265389
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
400201 -- Chemical & Physicochemical Properties
550200* -- Biochemistry
59 BASIC BIOLOGICAL SCIENCES
AZINES
BINDING ENERGY
BIOCHEMISTRY
CHEMICAL PREPARATION
CHEMICAL REACTIONS
CHEMISTRY
CONFORMATIONAL CHANGES
DNA
ENERGY
HETEROCYCLIC COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PYRIMIDINES
STEREOCHEMISTRY
SYNTHESIS