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 Chem., 46, 3483 and unpublished results) as rigid probes of DNA alkylation and crosslinking processes leading to cytotoxicity.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

Publication Date


Document Type


Student Type


Degree Name

Chemistry (MS)

Department, Program, or Center

School of Chemistry and Materials Science (COS)


Christian Reinhardt


Physical copy available from RIT's Wallace Library at QH445 .C32 1985


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