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A Proposed Model of the Interaction of 4-Nitroquinoline 1-Oxide with DNA¹

University of Texas Southwestern Medical School, Department of Pathology, and Laboratories for Cell Research, Woodlawn Hospital, Dallas, Texas 75219

Extended Huckel molecular orbital computations were performed on both carcinogenic and noncarcinogenic 4-nitroquinoline 1-oxides (4-NQO's) and related compounds. Distinct correlations between carcinogenicity and several molecular orbital characteristics were found. All correlations between molecular orbital properties and carcinogenicity were modified by one or more of the following structural factors: (a) the absence of a 4-nitro group, (b) the absence of a 1-oxide group, or (c) the presence of bulky substituents in position 2 or 3 of the quinoline ring. Any of the three factors resulted in either noncarcinogenicity or reduced carcinogenicity. Conformational studies indicated that the 4-nitro group was approximately 60° out of the plane of the quinoline ring and that the addition of an electron to 4-NQO was energetically probable.

4-Hydroxyaminoquinoline 1-oxide, a metabolic reduction product of 4-NQO, has been considered a possible proximal carcinogen. The theoretical ease of reduction of the nitroquinolines to the corresponding hydroxyaminoquinoline does not always parallel carcinogenicity.

A model of complex formation between deoxyguanosine in DNA and carcinogenic 4-NQO's and 4-hydroxyaminoquinoline 1-oxides was constructed based upon molecular orbital results and steric factors, which allowed the prediction of the qualitative carcinogenicity of 26 derivatives of 4-NQO. Carcinogenicity may result from complex formation of the 4-nitro derivatives and/or from the interaction of the 4-hydroxyaminoquinoline 1-oxides with DNA.

¹ This work was supported in part by research grants from the NIH (1 RO1 CA 11479-01 PTHB), Damon Runyon Memorial Fund (DRG-355G), National Aeronautics and Space Administration (NSG-210-62), Southwestern Medical Foundation, and the American Medical Association Education and Research Fund (3484-3).

² Recipient of USPHS Career Development Award 1-K4-CA-23, 087-01.

³ Recipient of USPHS Career Development Award 1-5-K3-GM-19, 909-02.

Received 6/12/70. Accepted 11/25/70.