A series of disubstituted 2-azaadamantanes representing conformationally defined nitrogen mustards incorporated into an adamantyl framework with fixed separation distances between alkylating centers of 3.5 Å. (1: 4,8-dichloro-2-azaadamantane) and 2.5 Å (2: 4,9-dichloro-2-azaadamantane; 3: 4, 10-dichloro-2-azaadamantane) have been synthesized (Henkel et al., (1981) J. Org. Chem., 46, 3483 and unpublished results) as rigid probes of DNA alkylation and crosslinking processes leading to cytotoxicity. Figure. 1. 4,8 dichloro-2-aza adamantane Figure. 2. 4,9 dichloro-2-aza adamantane Figure. 3. 4,10 dichloro-2-aza adamantane The extent of intermolecular DNA crosslinking by the N-methyl isomer series has been measured by an ethidium bromide fluorescence assay. Results indicate that isomers 1 and 2 form intermolecular DNA crosslinks, while 3 does not. Analysis of the kinetics of the reaction isotherms of 1 and 2 indicate significant differences in their rates and stability of crosslink formation. Crosslink reactions using DNAs of different base composition have established that the extent of crosslinking increases with increasing (G + C) content; however, the (G + C) dependence on crosslinking varies substantially between 1 and 2, and between the isomers and nitrogen mustard itself. A relationship also appears to exist between the cytotoxic activity and stereochemistry of the isomers, which may indeed reflect differences in the crosslinking behavior at the molecular level, and which may lead to further elucidation of the molecular mechanism of action of both the chloroethylnitrosoureas and the nitrogen mustards.
Library of Congress Subject Headings
Recombinant DNA; DNA
Department, Program, or Center
School of Chemistry and Materials Science (COS)
Cabral, Nancy A., "Molecular crosslinking of DNA by dichloro-n-methyl-azaadamantane isomers" (1985). Thesis. Rochester Institute of Technology. Accessed from
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