Genomes and Genes
folic acid antagonists
Summary: Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033)
- Zhou W, Viswanathan K, Hill D, Anderson A, Wright D. Acetylenic linkers in lead compounds: a study of the stability of the propargyl-linked antifolates. Drug Metab Dispos. 2012;40:2002-8 pubmed publisher..On the basis of the lessons of these metabolic studies, a more advanced inhibitor was designed, synthesized, and shown to have increased (t(1/2) = 65 min) metabolic stability while maintaining potent enzyme inhibition. ..
- Zander J, Besier S, Ackermann H, Wichelhaus T. Synergistic antimicrobial activities of folic acid antagonists and nucleoside analogs. Antimicrob Agents Chemother. 2010;54:1226-31 pubmed publisherThe antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues...
- O Connor O, Horwitz S, Hamlin P, Portlock C, Moskowitz C, Sarasohn D, et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol. 2009;27:4357-64 pubmed publisher..The duration of responses ranged from 3 to 26 months. Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma. ..
- Karema C, Imwong M, Fanello C, Stepniewska K, Uwimana A, Nakeesathit S, et al. Molecular correlates of high-level antifolate resistance in Rwandan children with Plasmodium falciparum malaria. Antimicrob Agents Chemother. 2010;54:477-83 pubmed publisher..13). The pfdhfr 164-Leu polymorphism is prevalent in eastern Rwanda. Antimalarial treatments with currently available antifol-sulfa combinations are no longer effective in Rwanda because of high-level resistance. ..
- Jayaraman P, Sakharkar K, Sing L, Chow V, Sakharkar M. Insights into antifolate activity of phytochemicals against Pseudomonas aeruginosa. J Drug Target. 2011;19:179-88 pubmed publisher..Taken together, the above findings provide novel insights to mode of interactions of these phytochemicals with antibiotics and may have significance as prospective leads in the development of antipseudomonal drug developments. ..
- Sáez Ayala M, Sánchez del Campo L, Montenegro M, Chazarra S, Tarraga A, Cabezas Herrera J, et al. Comparison of a pair of synthetic tea-catechin-derived epimers: synthesis, antifolate activity, and tyrosinase-mediated activation in melanoma. ChemMedChem. 2011;6:440-9 pubmed publisher..TMCG was also a better inhibitor of dihydrofolate reductase and was more efficiently oxidized by tyrosinase, potentially explaining the difference in activity between these epimers. ..
- Molina J. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment of several malignancies. IDrugs. 2008;11:508-21 pubmed..In contrast, for pralatrexate to be incorporated into the accepted treatment options for NSCLC, the drug will need to prove clear superiority to established agents. ..
- Deng Y, Zhou X, Kugel Desmoulin S, Wu J, Cherian C, Hou Z, et al. Synthesis and biological activity of a novel series of 6-substituted thieno[2,3-d]pyrimidine antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors over the reduced folate carrier and proton-coupled folate tr. J Med Chem. 2009;52:2940-51 pubmed publisher
- Paulsen J, Liu J, Bolstad D, Smith A, Priestley N, Wright D, et al. In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans. Bioorg Med Chem. 2009;17:4866-72 pubmed publisher..Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity. ..
- Bourne C, Wakeham N, Nammalwar B, Tseitin V, Bourne P, Barrow E, et al. Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase. Biochim Biophys Acta. 2013;1834:46-52 pubmed publisher..This directly contributes to the development of new antimicrobials, combating trimethoprim resistance, and treatment options for potential bioterrorism agents. ..
- Zakeri S, Motmaen S, Afsharpad M, Djadid N. Molecular characterization of antifolates resistance-associated genes, (dhfr and dhps) in Plasmodium vivax isolates from the Middle East. Malar J. 2009;8:20 pubmed publisher..vivax isolates are more exposed to SP and the selection or spread of resistant pvdhfr and pvdhps alleles might increase in the near future in this region. ..
- Somsak V, Uthaipibull C, Prommana P, Srichairatanakool S, Yuthavong Y, Kamchonwongpaisan S. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening. Malar J. 2011;10:291 pubmed publisher..vivax compounds targeting PvDHFR-TS. A similar approach could be used to generate transgenic models specific for other targets of interest, thus facilitating the development of anti-P. vivax drugs in general. ..
- Nair S, Miller B, Barends M, Jaidee A, Patel J, Mayxay M, et al. Adaptive copy number evolution in malaria parasites. PLoS Genet. 2008;4:e1000243 pubmed publisher..More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation. ..
- Sincak C, Schmidt J. Iclaprim, a novel diaminopyrimidine for the treatment of resistant gram-positive infections. Ann Pharmacother. 2009;43:1107-14 pubmed publisher..aureus and trimethoprim-, macrolide-, fluoroquinolone-, and glycopeptide-resistant strains. Additionally, in vitro activity similar to that of trimethoprim has been observed against gram-negative and atypical organisms. ..
- Prajapati S, Joshi H, Dev V, Dua V. Molecular epidemiology of Plasmodium vivax anti-folate resistance in India. Malar J. 2011;10:102 pubmed publisher..vivax in India, except Andaman and north-eastern state. The distinction of geographical regions with sensitive and resistant parasite phenotypes would be highly useful for designing and administering national anti-malarial drug policy. ..
- Auliff A, Adams J, O Neil M, Cheng Q. Defining the role of mutations in Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene using an episomal Plasmodium falciparum transfection system. Antimicrob Agents Chemother. 2010;54:3927-32 pubmed publisher..It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax. ..
- Tiwari R, Mahasenan K, Pavlovicz R, Li C, Tjarks W. Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex. J Chem Inf Model. 2009;49:1581-9 pubmed publisher..Binding energies predicted by all four programs were in accordance with experimental data. ..
- Izbicka E, Diaz A, Streeper R, Wick M, Campos D, Steffen R, et al. Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol. 2009;64:993-9 pubmed publisher..Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models. ..
- Zhang X, Zhou X, Kisliuk R, Piraino J, Cody V, Gangjee A. Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2011;19:3585-94 pubmed publisher
- Caspers P, Bury L, Gaucher B, Heim J, Shapiro S, Siegrist S, et al. In vitro and in vivo properties of dihydrophthalazine antifolates, a novel family of antibacterial drugs. Antimicrob Agents Chemother. 2009;53:3620-7 pubmed publisher..6 to 6.25 mg/kg. ..
- Mauritz R, Peters G, Kathmann I, Teshale H, Noordhuis P, Comijn E, et al. Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo. Cancer Chemother Pharmacol. 2008;62:937-48 pubmed publisher..Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved. ..
- Racanelli A, Rothbart S, Heyer C, Moran R. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 2009;69:5467-74 pubmed publisher..We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP. ..
- Gangjee A, Jain H, Phan J, Guo X, Queener S, Kisliuk R. 2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2010;18:953-61 pubmed publisher..This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR. ..
- Gonen N, Assaraf Y. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012;15:183-210 pubmed publisher..g. BGC 945). Hence, targeting mechanisms of antifolate-resistance could facilitate the development of rationally-based novel antifolates and strategies that overcome chemoresistance. ..
- Thomas H, Saravanan K, Wang L, Lin M, Northen J, Barlow H, et al. Preclinical evaluation of a novel pyrimidopyrimidine for the prevention of nucleoside and nucleobase reversal of antifolate cytotoxicity. Mol Cancer Ther. 2009;8:1828-37 pubmed publisher..Pharmacologically active concentrations of the inhibitors can be achieved in vivo using prodrug approaches, but greater potency is required to evaluate inhibition of nucleoside rescue as a therapeutic maneuver...
- Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez J, et al. Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol. 2008;73:1290-300 pubmed publisher
- Frey K, Liu J, Lombardo M, Bolstad D, Wright D, Anderson A. Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance. J Mol Biol. 2009;387:1298-308 pubmed publisher..The mutation induced equilibrium between two NADPH-binding conformations may contribute to decrease TMP binding and thus may be responsible for TMP resistance. ..
- Fossati E, Volpato J, Poulin L, Guerrero V, Dugas D, Pelletier J. 2-tier bacterial and in vitro selection of active and methotrexate-resistant variants of human dihydrofolate reductase. J Biomol Screen. 2008;13:504-14 pubmed publisher..The flexibility and robustness of this method will provide new insights into interactions between ligands and active-site residues of this clinically relevant human enzyme. ..
- Frey K, Georgiev I, Donald B, Anderson A. Predicting resistance mutations using protein design algorithms. Proc Natl Acad Sci U S A. 2010;107:13707-12 pubmed publisher..The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance. ..
- Lu F, Lim C, Nam D, Kim K, Lin K, Kim T, et al. Mutations in the antifolate-resistance-associated genes dihydrofolate reductase and dihydropteroate synthase in Plasmodium vivax isolates from malaria-endemic countries. Am J Trop Med Hyg. 2010;83:474-9 pubmed publisher..These findings suggests that the prevalence of mutations in pvdhfr and pvdhps in P. vivax isolates from different malaria-endemic countries is associated with selection pressure imposed by sulfadoxine-pyrimethamine. ..
- Viswanathan K, Frey K, Scocchera E, Martin B, Swain Iii P, Alverson J, et al. Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes. PLoS ONE. 2012;7:e29434 pubmed publisher..Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin...
- Nduati E, Diriye A, Ommeh S, Mwai L, Kiara S, Masseno V, et al. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitol Res. 2008;102:1227-34 pubmed publisher..For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria. ..
- Sánchez del Campo L, Otón F, Tarraga A, Cabezas Herrera J, Chazarra S, Rodriguez Lopez J. Synthesis and biological activity of a 3,4,5-trimethoxybenzoyl ester analogue of epicatechin-3-gallate. J Med Chem. 2008;51:2018-26 pubmed publisher..Disruption of the folate cycle by TMECG is a plausible explanation for its observed biological effects and suggests that, like other antifolate compounds, TMECG could be of clinical value in cancer therapy. ..
- Chan E, Cronstein B. Methotrexate--how does it really work?. Nat Rev Rheumatol. 2010;6:175-8 pubmed publisher..These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders. ..
- Deng Y, Wang Y, Cherian C, Hou Z, Buck S, Matherly L, et al. Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity. J Med Chem. 2008;51:5052-63 pubmed publisher..The combined properties of selective FR targeting, lack of RFC transport, and GARFTase inhibition resulting in potent antitumor activity are unprecedented and warrant development of these analogues as antitumor agents. ..
- Diop Bove N, Wu J, Zhao R, Locker J, Goldman I. Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line. Mol Cancer Ther. 2009;8:2424-31 pubmed publisher..Taken together, promoter silencing through methylation and gene copy loss accounted for the loss of PCFT activity in antifolate-resistant HeLa R1-11 cells. ..
- Kwon Y, Higgins M, Rabinowitz J. Antifolate-induced depletion of intracellular glycine and purines inhibits thymineless death in E. coli. ACS Chem Biol. 2010;5:787-95 pubmed publisher..Thus, E. coli has dual systems for surviving folate depletion and avoiding thymineless death: a short-term response based on sensing of amino acids and a long-term response based on sensing of nucleotides. ..
- Urquhart B, Gregor J, Chande N, Knauer M, Tirona R, Kim R. The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am J Physiol Gastrointest Liver Physiol. 2010;298:G248-54 pubmed publisher..Importantly, we note that PPI drug use appears to be associated with reduced hPCFT expression in vivo. ..
- Wright D, Anderson A. Antifolate agents: a patent review (2006 - 2010). Expert Opin Ther Pat. 2011;21:1293-308 pubmed publisher..Finally, a variety of new structures have been reported that may play an important role in the future development of therapeutic antifolates. ..
- Volpato J, Mayotte N, Fossati E, Guerrero V, Sauvageau G, Pelletier J. Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells. J Mol Recognit. 2011;24:188-98 pubmed publisher..We have thus demonstrated that bacterial selection of highly antifolate-resistant hDHFR variants can provide selectable markers for rapid ex vivo enrichment of hematopoietic cells. ..
- Wang L, Desmoulin S, Cherian C, Polin L, White K, Kushner J, et al. Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits. J Med Chem. 2011;54:7150-64 pubmed publisher
- Gangjee A, Li W, Yang J, Kisliuk R. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J Med Chem. 2008;51:68-76 pubmed..The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR. ..
- Nammalwar B, Bourne C, Bunce R, Wakeham N, Bourne P, Ramnarayan K, et al. Inhibition of bacterial dihydrofolate reductase by 6-alkyl-2,4-diaminopyrimidines. ChemMedChem. 2012;7:1974-82 pubmed publisher..These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR. ..
- Inoue K, Nakai Y, Ueda S, Kamigaso S, Ohta K, Hatakeyama M, et al. Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model. Am J Physiol Gastrointest Liver Physiol. 2008;294:G660-8 pubmed publisher..This study is the first to clone rPCFT/HCP1, and we successfully provided several lines of evidence that indicate its role as the molecular entity of the intestinal folate transport system. ..
- Bertino J. Cancer research: from folate antagonism to molecular targets. Best Pract Res Clin Haematol. 2009;22:577-82 pubmed publisher..MTX remains a potent and widely used agent. ..
- Gangjee A, Qiu Y, Li W, Kisliuk R. Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates. J Med Chem. 2008;51:5789-97 pubmed publisher..This study indicated that the 5-substituted 2-amino-4-oxo-6-methylthieno[2,3-d]pyrimidine scaffold is highly conducive to dual human TS-DHFR inhibitory activity. ..