folic acid antagonists

Summary

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)

Top Publications

  1. ncbi Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
    J Phan
    Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 92908, USA
    Biochemistry 40:1897-902. 2001
  2. ncbi Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines
    Esti Liani
    Department of Biology, The Technion, Haifa, Israel
    Int J Cancer 103:587-99. 2003
  3. ncbi Selection of antifolate-resistant Plasmodium falciparum by sulfadoxine-pyrimethamine treatment and infectivity to Anopheles mosquitoes
    Fabian Mendez
    Escuela de Salud Publica, Universidad del Valle, Cali, Colombia
    Am J Trop Med Hyg 77:438-43. 2007
  4. ncbi The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis
    Yehuda G Assaraf
    The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
    Drug Resist Updat 9:227-46. 2006
  5. ncbi 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
    Elisa Giovannetti
    Division of Pharmacology and Chemotherapy, Department of Internal Medicine, 55, Via Roma, 56126 Pisa, Italy
    Mol Pharmacol 73:1290-300. 2008
  6. ncbi Folic acid antagonists during pregnancy and the risk of birth defects
    S Hernandez-Diaz
    Slone Epidemiology Unit, Boston University School of Public Health, Brookline, Mass 02446, USA
    N Engl J Med 343:1608-14. 2000
  7. ncbi Tolerance is the key to understanding antimalarial drug resistance
    Ian M Hastings
    Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
    Trends Parasitol 22:71-7. 2006
  8. ncbi Neural tube defects in relation to use of folic acid antagonists during pregnancy
    S Hernandez-Diaz
    Slone Epidemiology Unit, Boston University School of Public Health, Brookline, MA 02446, USA
    Am J Epidemiol 153:961-8. 2001
  9. ncbi Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors
    A R Hanauske
    Eli Lilly and Company, Indianapolis, Indiana 46285, USA
    Oncologist 6:363-73. 2001
  10. pmc In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation
    Steven M Kiara
    Kenya Medical Research Institute KEMRI Wellcome Trust Collaborative Research Program, P O Box 230, 80108 Kilifi, Kenya
    Antimicrob Agents Chemother 53:3793-8. 2009

Detail Information

Publications276 found, 100 shown here

  1. ncbi Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
    J Phan
    Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 92908, USA
    Biochemistry 40:1897-902. 2001
    ..The thiophene ring of the drug is disordered between two parallel positions...
  2. ncbi Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines
    Esti Liani
    Department of Biology, The Technion, Haifa, Israel
    Int J Cancer 103:587-99. 2003
    ....
  3. ncbi Selection of antifolate-resistant Plasmodium falciparum by sulfadoxine-pyrimethamine treatment and infectivity to Anopheles mosquitoes
    Fabian Mendez
    Escuela de Salud Publica, Universidad del Valle, Cali, Colombia
    Am J Trop Med Hyg 77:438-43. 2007
    ..23, P < 0.05). Low-level drug resistance mutations have the potential to enhance transmission of P. falciparum and spread resistant parasites...
  4. ncbi The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis
    Yehuda G Assaraf
    The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion Israel Institute of Technology, Haifa, Israel
    Drug Resist Updat 9:227-46. 2006
    ....
  5. ncbi 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
    Elisa Giovannetti
    Division of Pharmacology and Chemotherapy, Department of Internal Medicine, 55, Via Roma, 56126 Pisa, Italy
    Mol Pharmacol 73:1290-300. 2008
    ....
  6. ncbi Folic acid antagonists during pregnancy and the risk of birth defects
    S Hernandez-Diaz
    Slone Epidemiology Unit, Boston University School of Public Health, Brookline, Mass 02446, USA
    N Engl J Med 343:1608-14. 2000
    ..We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations.
  7. ncbi Tolerance is the key to understanding antimalarial drug resistance
    Ian M Hastings
    Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
    Trends Parasitol 22:71-7. 2006
    ..This intermediate stage between fully sensitive and fully resistant parasites has far-reaching implications for the evolution of drug-resistant malaria...
  8. ncbi Neural tube defects in relation to use of folic acid antagonists during pregnancy
    S Hernandez-Diaz
    Slone Epidemiology Unit, Boston University School of Public Health, Brookline, MA 02446, USA
    Am J Epidemiol 153:961-8. 2001
    ..To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control ..
  9. ncbi Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors
    A R Hanauske
    Eli Lilly and Company, Indianapolis, Indiana 46285, USA
    Oncologist 6:363-73. 2001
    ..Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate...
  10. pmc In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation
    Steven M Kiara
    Kenya Medical Research Institute KEMRI Wellcome Trust Collaborative Research Program, P O Box 230, 80108 Kilifi, Kenya
    Antimicrob Agents Chemother 53:3793-8. 2009
    ..We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa...
  11. pmc Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure
    Mallika Imwong
    Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, National Science and Technology Development Agency, Bangkok, Thailand
    Antimicrob Agents Chemother 47:1514-21. 2003
    ..Highly mutated genes carry the S-->T rather than the S-->N mutation at residue 117. Mutations at residues 57 and 61 then occur, followed by a fifth mutation at residue 13...
  12. pmc Submicroscopic gametocytes and the transmission of antifolate-resistant Plasmodium falciparum in Western Kenya
    Mayke J A M Oesterholt
    Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    PLoS ONE 4:e4364. 2009
    ..In the present study, we determine the association between parasite mutations, submicroscopic P. falciparum gametocytemia and malaria transmission to mosquitoes...
  13. ncbi Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants
    Ilaria Badagnani
    Department of Biopharmaceutical Sciences, University of California, 1550 4th Street, Box 2911, San Francisco, CA 94158, USA
    J Pharmacol Exp Ther 318:521-9. 2006
    ..Furthermore, genetic variation in OATP1A2 may contribute to variation in MTX disposition and response...
  14. pmc Similar trends of pyrimethamine resistance-associated mutations in Plasmodium vivax and P. falciparum
    Mohammad Tauqeer Alam
    Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
    Antimicrob Agents Chemother 51:857-63. 2007
    ..vivax, suggesting that the drug should be used with caution to minimize the development of cross-species resistance in the field...
  15. ncbi 2-tier bacterial and in vitro selection of active and methotrexate-resistant variants of human dihydrofolate reductase
    Elena Fossati
    Departement de Biochimie, Universite de Montreal, Montreal, Quebec, Canada
    J Biomol Screen 13:504-14. 2008
    ..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...
  16. pmc Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes
    Shi Wu Wen
    University of Ottawa, Ont, Canada
    CMAJ 179:1263-8. 2008
    In previous studies, maternal exposure to folic acid antagonists was associated with increased risks of neural tube defects, cardiovascular defects, oral clefts and urinary tract defects...
  17. ncbi Dihydrofolate reductase inhibitors as antibacterial agents
    Stephen Hawser
    Arpida Ltd, Dammstrasse 36, 4142 Münchenstein, Switzerland
    Biochem Pharmacol 71:941-8. 2006
    ..Iclaprim, a recent example of a novel diaminopyrimidine currently in Phase III clinical trials, is also described together with several examples of anti-DHFR antibacterial compounds in pre-clinical development...
  18. ncbi Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells
    Jordan P Volpato
    Departement de Biochimie, Universite de Montreal, C P 6128, Succursale Centre Ville, Montreal, Quebec H3C 3J7, Canada
    J Mol Recognit 24:188-98. 2011
    ..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...
  19. ncbi Sulfadoxine-pyrimethamine, chlorproguanil-dapsone, or chloroquine for the treatment of Plasmodium vivax malaria in Afghanistan and Pakistan: a randomized controlled trial
    Toby Leslie
    HealthNet TPO Malaria and Leishmaniasis Control Programme, Peshawar, Northwest Frontier Province, Pakistan
    JAMA 297:2201-9. 2007
    ..The antifolates are an important and affordable antimalarial class to which it is often assumed P vivax malaria is intrinsically resistant...
  20. ncbi Effects of antifolates--co-trimoxazole and pyrimethamine-sulfadoxine--on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria
    A Sowunmi
    Department of Pharmacology and Therapeutics, Institute for Medical Research and Training, Ibadan, Nigeria
    Mem Inst Oswaldo Cruz 100:451-5. 2005
    ....
  21. pmc Targeting the proton-coupled folate transporter for selective delivery of 6-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of de novo purine biosynthesis in the chemotherapy of solid tumors
    Sita Kugel Desmoulin
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan, USA
    Mol Pharmacol 78:577-87. 2010
    ..Furthermore, they establish the feasibility of selective chemotherapy drug delivery via PCFT over RFC, a process that takes advantage of a unique biological feature of solid tumors...
  22. pmc Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex
    Rohit Tiwari
    Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA
    J Chem Inf Model 49:1581-9. 2009
    ..Binding energies predicted by all four programs were in accordance with experimental data...
  23. pmc 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
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA
    J Med Chem 51:68-76. 2008
    ..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...
  24. ncbi Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells
    R Zhao
    Department of Medicine, and the Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Chanin 2, 1300 Morris Park Ave, Bronx, NY10461, USA
    Biochem Pharmacol 61:857-65. 2001
    ..These data should be carefully considered in the design of regimens with antifolates, which incorporate co-administration of folates...
  25. ncbi Human reduced folate carrier: translation of basic biology to cancer etiology and therapy
    Larry H Matherly
    Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, The Cancer Biology Graduate Program, Detroit, MI 48201, USA
    Cancer Metastasis Rev 26:111-28. 2007
    ..Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma...
  26. pmc 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
    Kathleen M Frey
    Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA
    J Mol Biol 387:1298-308. 2009
    ..The mutation induced equilibrium between two NADPH-binding conformations may contribute to decrease TMP binding and thus may be responsible for TMP resistance...
  27. pmc Molecular epidemiology of Plasmodium vivax anti-folate resistance in India
    Surendra K Prajapati
    Genetics and Molecular Biology Laboratory, National Institute of Malaria Research NIMR, Sector 8, Dwarka, New Delhi 110077, India
    Malar J 10:102. 2011
    ..This study presents pattern of point mutations in dhfr/dhps genes among Indian sub-continent...
  28. pmc Molecular characterization of antifolates resistance-associated genes, (dhfr and dhps) in Plasmodium vivax isolates from the Middle East
    Sedigheh Zakeri
    Malaria and Vector Research Group MVRG, Biotechnology Research Center, Institut Pasteur of Iran, Tehran, Iran
    Malar J 8:20. 2009
    ..vivax infections are often exposed to sulphadoxine-pyrimethamine (SP). In the present study, the frequency distribution of mutations associated to SP resistance was investigated in pvdhfr and pvdhps genes from field isolates...
  29. ncbi Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications
    Shrikanta Chattopadhyay
    Departments of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine Cancer Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Mol Cancer Ther 6:404-17. 2007
    ..Laboratory studies are reviewed that raise the possibility of new approaches to the use of folic acid supplementation in clinical regimens with pemetrexed...
  30. ncbi Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression
    Eunice S Wang
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 6306, USA
    Leuk Lymphoma 44:1027-35. 2003
    ..These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation...
  31. ncbi Methotrexate--how does it really work?
    Edwin S L Chan
    Department of Medicine, New York University School of Medicine, 550 First Avenue, NBV16N1, New York, NY 10016, USA
    Nat Rev Rheumatol 6:175-8. 2010
    ..These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders...
  32. ncbi Basis for antifolate action and resistance in malaria
    Yongyuth Yuthavong
    National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Rama 6 Road, 10400, Bangkok, Thailand
    Microbes Infect 4:175-82. 2002
    ..New synergistic combinations of drugs targeting DHFR and dihydropteroate synthase may be employed, with new provisions against development of resistance...
  33. pmc Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis
    Aimable Nahimana
    Institute of Microbiology, University Hospital of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland
    Antimicrob Agents Chemother 48:4301-5. 2004
    ..The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance...
  34. pmc Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed
    Sang Hee Min
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Cancer Chemother Pharmacol 61:819-27. 2008
    ..These data indicate that caffeine and its analog, theobromine, may be a useful approach to enhance pemetrexed-based chemotherapy...
  35. ncbi Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction
    Andong Qiu
    Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Physiol Cell Physiol 293:C1669-78. 2007
    ..MmPCFT mRNA levels increased approximately 13-fold in the proximal small intestine in mice fed a folate-deficient vesus folate-replete diet, consistent with the critical role that PCFT plays in intestinal folate absorption...
  36. ncbi Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate
    D A Matthews
    Science 197:452-5. 1977
    ....
  37. pmc Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition
    Alexandra C Racanelli
    Department of Pharmacology and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298 0035, USA
    Cancer Res 69:5467-74. 2009
    ..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...
  38. ncbi Cancer research: from folate antagonism to molecular targets
    Joseph R Bertino
    Department of Molecular Therapeutics, The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
    Best Pract Res Clin Haematol 22:577-82. 2009
    ..MTX remains a potent and widely used agent...
  39. ncbi Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo
    Robert Mauritz
    Department of Medical Oncology, VU University Medical Center, P O Box 7057, 1007 MB, Amsterdam, The Netherlands
    Cancer Chemother Pharmacol 62:937-48. 2008
    ..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...
  40. ncbi Pharmacology and mechanism of action of pemetrexed
    Alex A Adjei
    Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
    Clin Lung Cancer 5:S51-5. 2004
    ..Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. In this review, the biochemistry and mechanism of action of pemetrexed are discussed...
  41. ncbi Molecular basis of antifolate resistance
    Yehuda G Assaraf
    The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion Israel Institute of Technology, Haifa, 32000, Israel
    Cancer Metastasis Rev 26:153-81. 2007
    ....
  42. ncbi Dihydrofolate reductase as a target for chemotherapy in parasites
    A Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
    Curr Pharm Des 13:609-39. 2007
    ..This review discusses the synthesis and structural requirements for selective DHFR inhibition and their relevance to parasitic chemotherapy, since 1995...
  43. ncbi Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts
    B A Teicher
    Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA
    Clin Cancer Res 6:1016-23. 2000
    ..Administration of MTA along with paclitaxel or doxorubicin resulted in additive MX-1 TGD. Thus, MTA appears to be especially effective in combination therapies including 5-fluorouracil or an antitumor platinum complex...
  44. ncbi Iclaprim, a novel diaminopyrimidine for the treatment of resistant gram-positive infections
    Carrie A Sincak
    College of Pharmacy, Midwestern University Chicago, Downers Grove, IL 60515, USA
    Ann Pharmacother 43:1107-14. 2009
    ..To review the pharmacology, microbiology, in vitro susceptibility, pharmacokinetics, clinical trial data, safety, and tolerability of iclaprim, a novel dihydrofolate reductase (DHFR) inhibitor...
  45. ncbi Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain
    David C M Chan
    Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Med Chem 48:4420-31. 2005
    ..avium DHFR (IC(50) = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR...
  46. ncbi Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
    J Med Chem 47:6893-901. 2004
    ..This supports our original hypothesis that truncation of the B-ring of a highly potent 6-6 ring system to a 6-5 ring system can be compensated by bridge homologation to restore the overall length of the molecule...
  47. pmc Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents: design, synthesis, and biological evaluation of classical and nonclassical pyrrolo[2,3-d]pyrimidine antifolates(1)
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
    J Med Chem 49:1055-65. 2006
    ..Compound 4 was not a substrate for human FPGS. Metabolite protection studies established TS as its principal target. Most of the nonclassical analogues were only inhibitors of human TS with IC(50) values of 0.23-26 microM...
  48. ncbi Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation
    J D Roberts
    Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 0037, USA
    Cancer Chemother Pharmacol 45:103-10. 2000
    ..Pharmacokinetic and metabolism studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics...
  49. pmc 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
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA
    J Med Chem 51:5789-97. 2008
    ..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...
  50. pmc 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 transpo
    Yijun Deng
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    J Med Chem 52:2940-51. 2009
    ....
  51. pmc Therapeutic targeting of a novel 6-substituted pyrrolo [2,3-d]pyrimidine thienoyl antifolate to human solid tumors based on selective uptake by the proton-coupled folate transporter
    Sita Kugel Desmoulin
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan, USA
    Mol Pharmacol 80:1096-107. 2011
    ..Our findings suggest exciting new therapeutic possibilities to selectively deliver novel antifolate drugs via transport by PCFT over RFC by exploiting the acidic tumor microenvironment...
  52. ncbi Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase
    Andre Rosowsky
    Dana Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Med Chem 47:2475-85. 2004
    ..26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX...
  53. ncbi Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function
    Julie L Bronder
    Department of Pharmacology and Toxicology, Massey Cancer Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA
    Cancer Res 62:5236-41. 2002
    ..We conclude that carcinoma cells are killed equally well by DDATHF and related compounds whether or not the p53 pathway is intact and that the utility of GART inhibitors would not be limited to p53-negative tumors...
  54. pmc Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
    J Med Chem 48:5329-36. 2005
    ..In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity...
  55. ncbi Drosophila dihydrofolate reductase mutations confer antifolate resistance to mammalian cells
    Joslynn G Affleck
    Department of Biology, Biosciences, Queen s University, Kingston, Ontario, Canada K7L 3N6
    Eur J Pharmacol 529:71-8. 2006
    ..Constructs using this substitution in combination with other Drosophila DHFR specific residues would make excellent candidates for gene therapy and genetic markers in the treatment of certain human disorders...
  56. ncbi Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis
    Phillip M Pelphrey
    Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA
    J Med Chem 50:940-50. 2007
    ..gondii) relative to trimethoprim were generated by synthesizing just 14 new analogues and by adding only a total of 52 Da to the mass of the parent compound, creating an efficient ligand as an excellent candidate for further study...
  57. pmc Mutations in the antifolate-resistance-associated genes dihydrofolate reductase and dihydropteroate synthase in Plasmodium vivax isolates from malaria-endemic countries
    Feng Lu
    Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea
    Am J Trop Med Hyg 83:474-9. 2010
    ..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...
  58. pmc Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1)
    Michele Visentin
    Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy
    Mol Pharmacol 81:134-42. 2012
    ..In contrast, the high affinity of this transporter for BSP relative to antifolates seems to be intrinsic to its binding site and independent of the proton concentration...
  59. ncbi A defect in the p53 response pathway induced by de novo purine synthesis inhibition
    Julie L Bronder
    Department of Pharmacology and Toxicology and the Massey Cancer Center, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298, USA
    J Biol Chem 278:48861-71. 2003
    ....
  60. pmc Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity
    Yijun Deng
    Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    J Med Chem 51:5052-63. 2008
    ..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...
  61. ncbi Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia
    Peter D Cole
    Pediatric Hematology Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School UMDNJ, 195 Little Albany Street, New Brunswick, NJ 08901, USA
    Cancer Chemother Pharmacol 62:65-75. 2008
    ..This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL...
  62. ncbi Selective preservation of pemetrexed pharmacological activity in HeLa cells lacking the reduced folate carrier: association with the presence of a secondary transport pathway
    Rongbao Zhao
    Departments of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, and the Einstein Cancer Research Center, Bronx, New York 10461, USA
    Cancer Res 64:3313-9. 2004
    ....
  63. pmc Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA
    J Med Chem 52:4892-902. 2009
    ..Some of the nonclassical analogues were potent and selective inhibitors of DHFR from Toxoplasma gondii...
  64. pmc 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 β-gl
    Lei Wang
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh 15219, Pennsylvania 15282, United States
    J Med Chem 54:7150-64. 2011
    ....
  65. pmc Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduc
    Lei Wang
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA
    J Med Chem 53:1306-18. 2010
    ..5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC...
  66. ncbi Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance
    Nitzan Gonen
    The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion Israel Institute of Technology, Haifa 32000, Israel
    Drug Resist Updat 15:183-210. 2012
    ..g. BGC 945). Hence, targeting mechanisms of antifolate-resistance could facilitate the development of rationally-based novel antifolates and strategies that overcome chemoresistance...
  67. pmc 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
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States
    Bioorg Med Chem 18:953-61. 2010
    ..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...
  68. ncbi Molecular characterization of dihydrofolate reductase in relation to antifolate resistance in Plasmodium vivax
    Ubolsree Leartsakulpanich
    National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Rama 6 Road, 10400, Bangkok, Thailand
    Mol Biochem Parasitol 119:63-73. 2002
    ..Data on kinetic parameters and inhibitory constant suggest that the wild-type P. vivax is susceptible to antimalarial antifolates and that point mutations in the DHFR domain of P. vivax are responsible for antifolate resistance...
  69. ncbi Phase I and pharmacokinetic study of LY309887: a specific inhibitor of purine biosynthesis
    D R Budman
    Don Monti Division of Oncology, North Shore University Hospital, New York University School of Medicine, Manhasset 11030, USA
    Cancer Chemother Pharmacol 47:525-31. 2001
    ..In this phase I trial in humans the safety and pharmacology of LY309887 on a weekly schedule combined with daily oral 5-mg doses of folic acid were evaluated...
  70. ncbi Mechanism of inhibition of wt-dihydrofolate reductase from E. coli by tea epigallocatechin-gallate
    Michele Spina
    Department of Molecular, Cellular and Animal Biology, University of Camerino, Via Gentile III da Varano, 62032, Camerino MC, Italy
    Proteins 72:240-51. 2008
    ..Collectively, our data have confirmed the selectivity of antifolate compounds with respect to the different source of enzyme (bacterial or mammalian DHFR) and the possible role of tea catechins as chemopreventive agents...
  71. ncbi The molecular identity and characterization of a Proton-coupled Folate Transporter--PCFT; biological ramifications and impact on the activity of pemetrexed
    Rongbao Zhao
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Cancer Metastasis Rev 26:129-39. 2007
    ....
  72. pmc Structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from cryptosporidium
    David B Bolstad
    Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA
    J Med Chem 51:6839-52. 2008
    ..Using the structures of both the protozoal and human enzymes, we have developed inhibitors with nanomolar potency (1.1 nM) against the pathogenic enzyme and high levels (1273-fold) of selectivity over the human enzyme...
  73. pmc Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening
    Voravuth Somsak
    Protein Ligand Engineering and Molecular Biology Laboratory, National Center for Genetic Engineering and Biotechnology BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand
    Malar J 10:291. 2011
    ..vivax parasites...
  74. ncbi Preclinical evaluation of a novel pyrimidopyrimidine for the prevention of nucleoside and nucleobase reversal of antifolate cytotoxicity
    Huw D Thomas
    Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK
    Mol Cancer Ther 8:1828-37. 2009
    ..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...
  75. pmc 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
    Xin Zhang
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
    Bioorg Med Chem 19:3585-94. 2011
    ....
  76. ncbi Insights into antifolate activity of phytochemicals against Pseudomonas aeruginosa
    Premkumar Jayaraman
    Biomedical Engineering Research Centre, Nanyang Technological University, Singapore
    J Drug Target 19:179-88. 2011
    ..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...
  77. pmc Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption
    Kris Mahadeo
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Physiol Cell Physiol 299:C1153-61. 2010
    ....
  78. pmc Synergistic antimicrobial activities of folic acid antagonists and nucleoside analogs
    Johannes Zander
    Institute of Medical Microbiology and Infection Control, Hospital of Goethe University, Paul Ehrlich Str 40, 60596 Frankfurt Main, Germany
    Antimicrob Agents Chemother 54:1226-31. 2010
    The antimicrobial activities of folic acid antagonists are supposed to be antagonized by elevated extracellular thymidine concentrations in damaged host tissues...
  79. ncbi Novel alleles of Plasmodium falciparum dhfr that confer resistance to chlorcycloguanil
    Sonia Y Hunt
    Department of Genome Sciences, University of Washington, Seattle, WA 98195 7730, USA
    Mol Biochem Parasitol 139:25-32. 2005
    ..The resulting allele, 16V/51I/59R/108T is highly resistant to chlorcycloguanil, but 200-fold more sensitive to pyrimethamine than the 51I/59R/108N allele...
  80. pmc Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells
    C Tekle
    Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
    Br J Cancer 99:750-9. 2008
    ....
  81. pmc Resistance to therapies for infection by Plasmodium vivax
    J Kevin Baird
    Eijkman Oxford Clinical Research Unit, Jalan Diponegoro No 69, Jakarta 10430, Indonesia
    Clin Microbiol Rev 22:508-34. 2009
    ....
  82. ncbi Amino acid mutations in Plasmodium vivax DHFR and DHPS from several geographical regions and susceptibility to antifolate drugs
    Alyson Auliff
    Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, QLD, Australia
    Am J Trop Med Hyg 75:617-21. 2006
    ..Parasites with the S58R/S117N dhfr allelic type showed an MIC level for pyrimethamine and cycloguanil comparable to that previously reported, but were susceptible to WR99210...
  83. ncbi DNA and RNA synthesis: antifolates
    Ivan M Kompis
    Arpida Ltd, Dammstrasse 36, 4142 Münchenstein, Switzerland
    Chem Rev 105:593-620. 2005
  84. ncbi LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes
    C Shih
    Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA
    Cancer Res 57:1116-23. 1997
    ..Therefore, our data suggest that LY231514 is a novel classical antifolate, the antitumor activity of which may result from simultaneous and multiple inhibition of several key folate-requiring enzymes via its polyglutamated metabolites...
  85. pmc Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers
    E Izbicka
    CTRC IDD, San Antonio, TX, USA
    Cancer Chemother Pharmacol 64:993-9. 2009
    ..This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed...
  86. ncbi Synthesis and biological activity of a 3,4,5-trimethoxybenzoyl ester analogue of epicatechin-3-gallate
    Luis Sánchez-del-Campo
    Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia, Spain
    J Med Chem 51:2018-26. 2008
    ..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...
  87. ncbi Antifolates can have a role in the treatment of Plasmodium vivax
    Vivian N Hawkins
    Department of Genome Sciences, University of Washington, Box 355065, Seattle, WA 98195, USA
    Trends Parasitol 23:213-22. 2007
    ..Other studies have examined the impact of dhps genotype on response to sulfadoxine. These data indicate that, under certain circumstances, SP could be a valuable tool in the fight against P. vivax...
  88. ncbi Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma
    Owen A O'Connor
    Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, NY 10032, USA
    Br J Haematol 139:425-8. 2007
    ..For each TCL patient, the response was more durable than their best response with chemotherapy. This early experience is the first to document this unique activity of pralatrexate in TCL...
  89. pmc Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer
    Eunice Nduati
    Kenya Medical Research Institute Wellcome Trust Collaborative Research Program, PO Box 230, 80108 Kilifi, Kenya
    Parasitol Res 102:1227-34. 2008
    ..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...
  90. pmc The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier
    Rongbao Zhao
    Departments of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
    Mol Pharmacol 74:854-62. 2008
    ....
  91. ncbi Kinetic properties of dihydrofolate reductase from wild-type and mutant Plasmodium vivax expressed in Escherichia coli
    R Tahar
    , Centre National de la Recherche Scientifique, 91198, Gif-sur-Yvette, France
    Mol Biochem Parasitol 113:241-9. 2001
    ..The kinetics of enzyme inhibition indicated that point mutations (Ser58Arg and Ser117Asn) are associated with lower affinity between the mutant enzyme and pyrimethamine and cycloguanil, which may be the origin of antifolate resistance...
  92. ncbi Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors
    B van Triest
    Department of Oncology, University Hospital VU, Amsterdam, The Netherlands
    Ann Oncol 11:385-91. 2000
    ..This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease...
  93. pmc 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
    Owen A O'Connor
    Lymphoid Development and Malignancy Program, Lymphoma Service, Columbia University, Herbert Irving Comprehensive Cancer Center, 1130 St Nicholas Ave, New York, NY 10032, USA
    J Clin Oncol 27:4357-64. 2009
    ..To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma...
  94. ncbi Crystal structure of avian dihydrofolate reductase containing phenyltriazine and NADPH
    K W Volz
    J Biol Chem 257:2528-36. 1982
  95. pmc Molecular surveillance of drug resistance through imported isolates of Plasmodium falciparum in Europe
    Tomas Jelinek
    Department of Infectious Diseases and Tropical Medicine, University of Munich, Leopoldstr, 5, 80802 Munich, Germany
    Malar J 1:11. 2002
    ..The screening results were used to map the prevalence of mutations and, thus, levels of potential drug resistance in endemic areas world-wide...
  96. ncbi Fitness effects of DHFR-TS mutations associated with pyrimethamine resistance in apicomplexan parasites
    Leah M Fohl
    Department of Biology, University of Pennsylvania, Philadelphia, PA 19104 6018, USA
    Mol Microbiol 50:1319-27. 2003
    ..A sensitive PCR-based assay permits different growth rates to be assessed even in the absence of a drug resistance marker that can be scored by plaque assay...
  97. ncbi Kinetics of the inhibition of bovine liver dihydrofolate reductase by tea catechins: origin of slow-binding inhibition and pH studies
    Enma Navarro-Perán
    Grupo de Investigacion de Enzimologia, Departamento de Bioquimica y Biologia Molecular A, Facultad de Biologia, Universidad de Murcia, Murcia, Spain
    Biochemistry 44:7512-25. 2005
    ..The physiological implications of these pH dependencies are also discussed...
  98. ncbi Translational up-regulation of antifolate drug targets in the human malaria parasite Plasmodium falciparum upon challenge with inhibitors
    Niroshini Nirmalan
    Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology UMIST, P O Box 88, Manchester M60 1QD, UK
    Mol Biochem Parasitol 136:63-70. 2004
    ....
  99. ncbi Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression
    Jennifer Sigmond
    Department of Medical Oncology, VU University Medical Center, P O Box 7057, 1007 MB Amsterdam, The Netherlands
    Biochem Pharmacol 66:431-8. 2003
    ....
  100. ncbi Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria
    Peter Schneider
    Arpida Ltd, Dammstrasse 36, CH 4142, Muenchenstein, Switzerland
    Bioorg Med Chem Lett 13:4217-21. 2003
    ..This compound is active against methicillin, TMP and vancomycin resistant strains. Arpida Ltd. is developing Iclaprim for serious hospital infections from Gram-positive pathogens and respiratory tract infections...
  101. ncbi Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors
    Y Yuthavong
    National Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Science Park, Pathumthani 12120, Thailand
    Parasitology 130:249-59. 2005
    ..falciparum bearing the mutant enzymes...

Research Grants57

  1. Novel Single, Dual and Multitargeted Inhibitors of RTKs
    Aleem Gangjee; Fiscal Year: 2007
    ..abstract_text> ..
  2. Antitumor Antimitotics That Reverse Tumor Resistance
    Aleem Gangjee; Fiscal Year: 2010
    ..The study will also further define the mechanism of action of the novel series and could afford agents for clinical use. ..
  3. Alpha Folate Receptor Mediated GARFTase Inhibitors as Selective Antitumor Agents
    Aleem Gangjee; Fiscal Year: 2010
    ....
  4. STRUCTURE BASED ANALOGS AS ANTIOPPORTUNISTIC AGENTS
    Aleem Gangjee; Fiscal Year: 2001
    ..The analogues synthesized will also be submitted for screening against tuberculosis (NIAID) parasitic diseases (WHO) and tumor cells in culture (NCI). ..
  5. NOVEL NONINDUCIBLE THYMIDYLATE SYNTHASE INHIBITORS
    Aleem Gangjee; Fiscal Year: 2004
    ....
  6. Single Agents with Designed Combination Chemotherapy Potential
    Aleem Gangjee; Fiscal Year: 2010
    ..abstract_text> ..
  7. Third Generation Antiopportunistic Agents
    Aleem Gangjee; Fiscal Year: 2003
    ..Screening against tuberculosis (NIAID) and tumor cells in culture (NCI) is also proposed. ..
  8. Novel, P. jirovecii Specific Antipneumocystis Agents
    Aleem Gangjee; Fiscal Year: 2009
    ..These agents could be used alone or in combination to treat PCP thus providing novel agents against a new target. ..
  9. CONTROL OF FOLIC ACID METABOLISM IN MAMMALS
    Robert Steele; Fiscal Year: 1991
    ..and other cases of rapid cell division and growth such as cancer: many cancer chemotherapeutic agents are folic acid antagonists. We have discovered that altered flow through the one-carbon pool brought about by altered vitamin A ..
  10. PATHOPHYSIOLOGY & CHEMOTHERAPY IN PSORIASIS AND CANCER
    Gerald Weinstein; Fiscal Year: 1991
    ..The basic cellular mechanisms by which the folic acid antagonists and inhibitors of polyamine biosynthesis selectively influence epidermal hyperproliferation in the ..
  11. Structural Studies of AIDS-Responsive Drugs
    Vivian Cody; Fiscal Year: 2010
    ..These results will help guide the design of species selective inhibitors. Mutagenesis studies will be carried out to test these possibilitiesin the structure-based correlations to help design novel pjDHFRinhibitors. ..
  12. NOVEL APPROACHES TO ANTIFOLATE CHEMOTHERAPY
    Andre Rosowsky; Fiscal Year: 2003
    ..The focus will be on enhancing polyglutamation of the lead compound dmAMT by modification of the B-ring and/or pABA moiety. ..
  13. LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS
    Andre Rosowsky; Fiscal Year: 2004
    ..Analogs of PT653 with a COOH, NH2, or OH group on the tricyclic moiety, and prodrugs thereof, will be made with the goal of improving aqueous solubility without sacrificing potency or selectivity. ..
  14. FOLYLPOLYGLUTAMATE SYNTHETASE IN CANCER CHEMOTHERAPY
    John McGuire; Fiscal Year: 2003
    ..This may explain why high-level resistance to pulse MTX can occur in the absence of a large decrease in total FPGS activity or a rise in glutamyl hydrolase activity. ..
  15. Enhancement of methotrexate uptake in childhood ALL
    John McGuire; Fiscal Year: 2009
    ..If successful, this research could provide a way to increase the effectiveness of methotrexate, a key drug used in treating childhood acute lymphoblastic leukemia, and thus increase the cure rate in this disease. ..
  16. TS PROPHYLAXIS AND DRUG-RESISTANT MALARIA IN MALAWI
    CHRISTOPHER PLOWE; Fiscal Year: 2007
    ..unreadable] [unreadable]..
  17. GLYCOSYLTRANSFERASES AS DRUG TARGETS IN MYCOBACTERIA
    Robert Reynolds; Fiscal Year: 2002
    ..These compounds will be screened in vitro using a broth dilution assay and cell-free assay transferase. Selected active compounds will be screened in vitro and in vivo in a macrophage assay and a murine TB model, respectively. ..
  18. Inhibitor of FtsZ Polymerization in M. tuberculosis
    Robert Reynolds; Fiscal Year: 2004
    ..Data from the biological screening and the EM structural studies will feed back into compound design in an interactive, iterative drug design cycle that critically focuses on antibacterial potency and selectivity. ..
  19. Mechanism of Action of Folate Antagonist
    Joseph Bertino; Fiscal Year: 2008
    ..The use of MEF cells null for p53, p19 ARF and both will be utilized to test in a more well defined system the function of these proteins on DHFR levels. ..
  20. FolK, a Mycobacterium tuberculosis Drug Target
    WILLIAM SULING; Fiscal Year: 2004
    ..It will also provide purified HPPK for future drug discovery studies based upon structure-activity relationships, molecular modeling and crystallographic structure-based drug design. ..
  21. Randomized, controlled trial of daily trimethoprim-sulfamethoxazole or weekly chl
    CHRISTOPHER PLOWE; Fiscal Year: 2008
    ..unreadable] [unreadable] [unreadable]..
  22. Crystallization of the Galactosyltransferase from Mtb
    Robert Reynolds; Fiscal Year: 2002
    ..This effort, however, is innovative in the choice of target and the impact that structural biology can have on our funded program. ..
  23. DRUG-RESISTANT MALARIA IN MALAWI
    CHRISTOPHER PLOWE; Fiscal Year: 2002
    ..abstract_text> ..
  24. TS PROPHYLAXIS AND DRUG-RESISTANT MALARIA IN MALAWI
    CHRISTOPHER PLOWE; Fiscal Year: 2003
    ....
  25. DIHYDRONEOPTERIN ALDOLASE, A TUBERCULOSIS DRUG TARGET
    WILLIAM SULING; Fiscal Year: 2002
    ..It will also provide purified DHNA for future drug discovery studies based upon structure-activity relationships, molecular modeling and crystallographic structure-based drug design. ..
  26. Role of Acetaldehyde in Alcoholic Cardiomyopathy
    Jun Ren; Fiscal Year: 2008
    ..Our long-term goal is to establish the toxic mechanism of acetaldehyde in the development of alcoholic cardiomyopathy so that prevention and treatment can be optimized [unreadable] [unreadable]..
  27. DENDRITIC CELL THERAPY OF CHRONIC MYELOGENOUS LEUKEMIA
    Mark Litzow; Fiscal Year: 2003
    ..The combined data will provide a comprehensive understanding of the interaction of the immune system and CML and will yield information required for the rational design of more effective clinical protocols in the future. ..
  28. Pilot study on the safety and efficacy of ciprofloxacin for prophylactic preventi
    Hans Herfarth; Fiscal Year: 2008
    ..unreadable] [unreadable] [unreadable]..
  29. NUCLEOTIDE DEPRIVATION-BASED SELECTIVE THERAPEUTICS
    RICHARD MORAN; Fiscal Year: 2008
    ..These studies are a logical extension of past studies supported by this grant, but also represent new directions to therapeutics suggested by recent advances in cancer cell biology. ..
  30. HUMAN MITOCHONDRIAL FOLATE/ANTIFOLATE TRANSPORT
    RICHARD MORAN; Fiscal Year: 2008
    ..abstract_text> ..
  31. VIBRATIONAL AND DYNAMICAL STUDIES OF ENZYMES
    Robert Callender; Fiscal Year: 2002
    ....
  32. Prostaglandin Synthesis, Genetics and Colorectal Cancer
    Cornelia M Ulrich; Fiscal Year: 2010
    ..They will also advance tailoring of chemoprevention in a way that maximizes benefit and minimizes toxicity. ..
  33. Imaging Enzyme Structure and Dynamics: Specific Function and Functional Diversity
    Hua Deng; Fiscal Year: 2010
    ..The fruits of this work can lead to more thoroughly understanding disease and then to the discovery of new drugs and methods as well as laboratory diagnostic methods. ..
  34. THYMIDYLATE SYNTHASE
    Robert Stroud; Fiscal Year: 2001
    ..Irwin Kunts, UCSF. Some mechanistic question will be approached using NMR spectroscopy in collaboration with Dr. Thomas James, UCSF. ..
  35. NSAID and COX/PG Metabolism and Colorectal Cancer
    Cornelia Ulrich; Fiscal Year: 2009
    ..Ultimately, such information on the metabolic variation will be useful in optimizing NSAIDs and NSAID regimens and will allow individual tailoring of chemoprevention. ..
  36. GENERAL CLINICAL RESEARCH CENTER
    Karen Antman; Fiscal Year: 2008
    ..abstract_text> ..
  37. Exercise effects on oxidative damage among women
    Cornelia Ulrich; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable] [unreadable]..
  38. POLYMORPHISMS IN PG/COX PATHWAY AND COLORECTAL POLYPS
    Cornelia Ulrich; Fiscal Year: 2003
    ..Finally, we plan to develop a model for integrating information on genetic variability at multiple points in this metabolic pathway. ..
  39. STRUCTURE BASED DRUG DESIGN
    Robert Stroud; Fiscal Year: 2004
    ..Public domain access to the structures of therapeutic targets and technology will encourage their use by major pharmaceutical companies for the better design of therapeutics. ..
  40. Role of 10-formyldihydrofolate in purine biosynthesis
    Tsunenobu Tamura; Fiscal Year: 2004
    ..If this pathway is proven, derivatives of 10-HCO-H2folate could be used to inhibit de novo purine biosynthesis for developing new anticancer drugs. ..
  41. Flavocoxid: A Medical Food Therapy for Osteoarthritis
    Sarah Morgan; Fiscal Year: 2004
    ..This innovative compound has commercial potential with its expected efficacy comparable to or exceeding the currently marketed COX inhibitors but with fewer side effects and at a significantly lower cost. ..
  42. Narrow-Spectrum Drug Targets for Bacillus anthracis
    WILLIAM BARROW; Fiscal Year: 2004
    ....
  43. Fostriecin and Related Protein Phosphatase Inhibitors
    Dale Boger; Fiscal Year: 2005
    ....
  44. 2005 Mechanisms of Membrane Transport Gordon Conference
    Robert Stroud; Fiscal Year: 2005
    ..abstract_text> ..
  45. Molecular Basis for Transmembrane Conduction & Signaling
    Robert Stroud; Fiscal Year: 2006
    ..A further aim is to improve crystals of the Acetylcholine receptor as a means of three-dimensional structure determination of an archetype of gating mechanisms in an archetype of neuroreceptor superfamilies. ..
  46. Anticancer Agent Pharmacodynamics in Acute Leukemia
    Mary Relling; Fiscal Year: 2006
    ..Our long- term goal is to identify host- and treatment-related risk factors for t-AML so that we can design less leukemogenic anticancer treatment regimens, with improved efficacy for the primary ALL. ..
  47. Modulation of NHE Activity by EPEC Infection
    Pradeep Dudeja; Fiscal Year: 2006
    ..Our findings may aid in the future development of improved therapeutic modalities for infectious diarrhea. [unreadable] [unreadable] [unreadable]..
  48. Modeling Folate, One-Carbon Metabolism & DNA Methylation
    Cornelia Ulrich; Fiscal Year: 2007
    ..We plan to make the model generally available to the research community, and anticipate that it will become a useful tool that can be used as an adjunct to experimental investigations and as an aid to study design. ..
  49. Simple, Selective Antimitotic Antiparasitic Agents
    Karl Werbovetz; Fiscal Year: 2007
    ..abstract_text> ..
  50. SIGNAL SEQUENCE RECOGNITION AND PROTEIN TARGETING
    Robert Stroud; Fiscal Year: 2007
    ..These will instruct in the mechanism of replacing the role of RNA by protein, and therefore in the essence of the dynamic roles of SRP RNA and cpSRP43. ..
  51. Genetic Study of Prostaglandin Synthesis/EGFR and Risk of Colorectal Neoplasia
    Cornelia Ulrich; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable]..
  52. IGF-1, Oxidative Stress and Cardiovascular Aging
    Jun Ren; Fiscal Year: 2002
    ..Our long-term goal is to establish the causal link among IGF-1 deficiency, enhanced oxidative damage and ventricular dysfunction in the progression of cardiovascular aging so that hormonal or antioxidant therapy can be optimized...
  53. PHOSPHOLIPASE ACTIVATION BY G-PROTEIN-LINKED RECEPTORS
    Alex Brown; Fiscal Year: 2004
    ..These studies will utilize both intact cells and cell-free preparations that retain purinergic receptor-stimulated activation of PLD1. ..