Dihydrofolate reductase inhibitor

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A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.

Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing.[1][2] Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents.[3]

Tetrahydrofolate synthesis pathway

Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline & diaminopyrroloquinazoline,[4] diaminopyrimidine, diaminopteridine and diaminotriazines.[5] The examples provided below are specific molecules belonging to one of the above-mentioned classes.

A variety of drugs act as inhibitors of dihydrofolate reductase:

References[edit]

  1. ^ Huennekens FM (1994). "The methotrexate story: a paradigm for development of cancer chemotherapeutic agents". Advances in Enzyme Regulation. 34: 397–419. doi:10.1016/0065-2571(94)90025-6. PMID 7942284. 
  2. ^ McGuire JJ (2003). "Anticancer antifolates: current status and future directions". Current Pharmaceutical Design. 9 (31): 2593–613. doi:10.2174/1381612033453712. PMID 14529544. 
  3. ^ Hawser S, Lociuro S, Islam K (March 2006). "Dihydrofolate reductase inhibitors as antibacterial agents". Biochemical Pharmacology. 71 (7): 941–8. doi:10.1016/j.bcp.2005.10.052. PMID 16359642. 
  4. ^ Srinivasan B, Skolnick J (May 2015). "Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors". The FEBS Journal. 282 (10): 1922–38. doi:10.1111/febs.13244. PMC 4445455Freely accessible. PMID 25703118. 
  5. ^ Srinivasan B, Tonddast-Navaei S, Skolnick J (October 2015). "Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase". European Journal of Medicinal Chemistry. 103: 600–14. doi:10.1016/j.ejmech.2015.08.021. PMID 26414808. 
  6. ^ Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R (March 2008). "Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo". PLoS Neglected Tropical Diseases. 2 (3): e190. doi:10.1371/journal.pntd.0000190. PMC 2254147Freely accessible. PMID 18320016. 
  7. ^ de Wit R, Kaye SB, Roberts JT, Stoter G, Scott J, Verweij J (February 1993). "Oral piritrexim, an effective treatment for metastatic urothelial cancer". British Journal of Cancer. 67 (2): 388–90. doi:10.1038/bjc.1993.71. PMC 1968166Freely accessible. PMID 8431372.