A systematic study will be made of the chemistry of O- substituted aryl hydroxamic acids. These are precursors to nitrenium ions which are generally regarded as the reactive intermediates involved in adduct formation between these carcinogens and DNA. Current research into the structure, conformation and biological consequences of many of these adducts is hampered by the lack of suitable general procedures for their synthesis in milligram quantities. In this proposal we describe steps we plan in order to overcome these limitations. Our selection of nucleophiles to use in these reactions will be guided by current interest in the adducts which should result. Deoxyguanosine and derivatives will be the primary targets, with dA and other bases taking a secondary role. Considerable emphasis will be placed on variation of the leaving groups on nitrogen. In the proposal we discuss why this is important, and in what ways the leaving group needs to be modified. In particular we propose to examine substrate in which the leaving group is a) p-nitrophenolate and derivatives, b) N- methyl-4-pyridone, and c) phosphine-oxide derivatives. The effect of changing the reaction medium will also be explored. It is discussed in the proposal how medium changes might be expected to favor the synthesis of adducts in which the carcinogen is bound to either the 0-6 or N-2 position of guanosine. These reaction sites lead to interesting, but, to date, rather inaccessible, adducts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA047599-01
Application #
3191329
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Arts and Sciences
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012