Investigations on the biological properties of the lipophilic DHFR-inhibitory benzoprims reveal non-folate modes of action and opportunities for anti-cancer drug design.
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.
Croughton
K A
KA
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, UK.
Matthews
C S
CS
Griffin
R J
RJ
Stevens
M F
MF
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000188:drug therapy; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000494:pharmacology; D010363:Pattern Recognition, Automated; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D008055:Lipids; D011743:Pyrimidines; C064625:methylbenzoprim; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate