Mechanism inspired development of rationally designed dihydrofolate reductase inhibitors as anticancer agents.

Abstract

On the basis of structural analysis of dihydrofolate reductase (DHFR) (cocrystallized separately with NADPH, dihydrofolate and NADPH, trimethoprim), compounds 2 and 3 were optimized for inhibition of DHFR. Appreciable tumor growth inhibitory activities of compounds 2 and 3 over 60 human tumor cell lines were recorded. Combination of syringaldehyde and indole moieties in these two compounds was rationalized by the synthesis of compounds 4-7, 10, and 11, which were found to have less tumor growth inhibitory activities than compounds 2 and 3. Further, UV-vis and NMR spectral investigations showed significant interactions of compounds 2 and 3 with DHFR and inhibition of its catalytic activity was observed in the presence of these compounds. Therefore, modification of trimethoprim, an antibacterial drug with no tumor growth inhibition, led to the development of compounds 2 and 3 having appreciable anticancer activities that seem to be due to inhibition of DHFR.

• Authors: Palwinder Singh, Matinder Kaur, Shaveta Sachdeva
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 14 Pg. 6381-90 (Jul 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22734697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzaldehydes
• Folic Acid Antagonists
• Indoles
• Pyrimidines
• syringaldehyde
• indole
• Tetrahydrofolate Dehydrogenase
• pyrimidine

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzaldehydes (chemistry)
• Cell Line, Tumor
• Drug Design
• Folic Acid Antagonists (chemical synthesis, chemistry, pharmacology)
• Humans
• Indoles (chemistry)
• Models, Molecular
• Protein Conformation
• Pyrimidines (chemistry)
• Tetrahydrofolate Dehydrogenase (chemistry, metabolism)