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Lookup NU author(s): Professor Roger Griffin
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Dichlorobenzoprim and methylbenzoprim were the lead compounds to emerge from investigations on a series of lipophilic 2,4-diamino-5-aryl-6-ethylpyrimidines synthesized and evaluated for their inhibition of dihydrofolate reductase (DHFR). Here the results of further mechanism-of-action studies are summarized. As expected, growth inhibitory activity of these compounds in the National Cancer Institute 60-cell-line screen correlated positively with DHFR enzyme inhibitory activity. Interestingly, two other aspects of their activity have been revealed. First, as evidenced by reversal experiments using hypoxanthine and thymidine, the two compounds, dichlorobenzoprim and methylbenzoprim, have been shown to exert an additional non-folate mechanism. Secondly, by exploitation of the COMPARE algorithm, a positive correlation has been established between the activity of certain members of this series and the existence of a mutation in the Ki-ras gene of non-small-cell lung and colon cancer cell lines. These observations have suggested that modification of the lead structures may offer opportunities to generate novel molecules without DHFR-inhibitory activity, but which may interact with new molecular targets for anti-cancer drug design.
Author(s): Griffin RJ; Croughton KA; Matthews CS; Stevens MFG
Publication type: Article
Publication status: Published
Journal: Anti-Cancer Drug Design
Year: 2001
Volume: 16
Issue: 2
Pages: 119-128
ISSN (print): 0266-9536
ISSN (electronic): 1460-2148
Publisher: Cognizant Communication Corp.
