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Dr. Roy L. Kisliuk

Stearns 705A
136 Harrison Ave.
Boston, MA 02111
roy.kisliuk@tufts.edu

office: 617-636-6869

Dr. Roy L. Kisliuk, Ph.D.

Professor Emeritus, Tufts Department of Biochemistry

 

Links:

Research

Lab Members

Recent Publications

  

Research Summary:

Work in Dr. Kisliuk's laboratory concerns the evaluation of antifolates as anticancer and ntiparasitic agents. The target enzymes are dihydrofolate reductase and thymidylate synthase, enzymes whose inhibition leads to cell death. The potential inhibitors are synthesized at Duquense University in the laboratory of Professor Aleem Gangjee. Some of the compounds selected from our enzyme screen are potent, selective inhibitors of cancer cell lines. Others are highly selective against enzymes from Toxoplasma gondii and Escherichia coli. An important theme in our current work is the identification of inhibitors with more than one site of action such as dual inhibitors of dihydrofolate reductase and thymidylate synthase. Two such compounds have recently been identified.

Research:


 

For more details, please see the publications below.

Lab Members

Recent Publications

  1. Gangjee, A., Wei, L., Yang, J., Kisliuk, R.L. 2007. "Design, Synthesis and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methyl-pyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors" J.Med. Chem. (In press)
  2. Reynolds, R.C., Campbell, S.R., Fairchild, R.G., Kisliuk, R.L. Micca, P.L., Queener, S.F., Riordan, J.M., Sedwick, W.D., Waud, W.R., Leung, A.K.W., Dixon, R.W., Suling, W.J., and Borhani D.W., 2007. Novel Boron-Containing, Nonclassical Antifolates: Synthesis and Preliminary Biological and Structural Evaluation. J. Med. Chem. 50: 3283-3289.
  3. Gangjee, A., Zeng, Y.,Talreja, T., McGuire, J.J., Kisliuk, R.L., and Queener, S.F. 2007. Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates
    J. Med. Chem.; 50: 3046 – 3053.
  4. Gangjee, A., Wang,Y., Queener, S.F., and Kisliuk, R.L. 2006. Synthesis of 2,6-Diamino-5-[(2-substituted phenylamino)]pyrimidin-
    4(3H)one as Inhibitors of Folate Metabolizing Enzymes.
    J. Heterocyclic Chem. 43: 1523-1531.
  5. Gangjee, A., Yang, J., McGuire, J.J., and Kisliuk, R.L. 2006. Synthesis and Evaluation of a Classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-subtituted-pyrrolo[2,3-d]pyrimidine as Anti-
    folates. Bioorganic and Medicinal Chemistry 14: 8590-8598.
  6. Kisliuk, R.L. 2006. Invited Articles on "Folates" and on "Thymidylate Synthesis" in " Encyclopedia of Life Sciences. John Wiley & Sons, Ltd., Chichester, UK (ELS at www.els.net) Gangjee, A., Jain, H.D., Phan, J., Lin, X., Song, X., McGuire, J.J. and Kisliuk, R.L. 2006 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. J. Med. Chem. 49; 1055-1065.
  7. Kisliuk, R.L. (2006) Invited Article on “Folates” in Encyclopediaof Life Sciences, John Wiley & Sons, Ltd., Chichester, UK
  8. Kisliuk, R.L. (2006) Invited Article on “Thymidylate Synthesis” in Encyclopedia of Life Sciences, John Wiley & Sons, Ltd., Chichester, UK
  9. Gangjee, A., Jain, H.D., Phan, J., Lin, X., Song, X., McGuire, J.J.and Kisliuk, R.L. (2006) Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase as Anbtitumor Agents: Design, Synthesis and Biological Evaluation of Classical and Nonclassical Pyrrolo[2,3-d]pyrimidine Antifolates. J. Med. Chem. 49; 1055-1065.
  10. Gangjee, A., Lin, X., Kisliuk, R.L., McGuire, J.J. 2005. Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2-3d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents. J. Med. Chem. 48: 7215-7222.
  11. Gangjee, A., Jain, H.D., Phan, J., Kisliuk, R.L. 2005. Synthesis of 2-Amino-4-oxo-5-substitiuted benzylthiopyrrolo[2,3-d]pyrimidines as Potential Inhibitors of Thymidylate Synthase. J. Heterocyclic Chem. 42: 165-168.
  12. Gangjee, A., Zeng, Y., McGuire, J.J. Kisliuk, R.L. 2005. Synthesis of Classical, Four-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine Analogues as Antifolates. J. Med. Chem. 48: 5329---5336.
  13. Gangjee, A., Zeng, Y., Ihnat, M., Warnke, L.A., Green, D.W., Kisliuk, R.L., Lin, F-T. 2005. Novel 5-Substituted, 2, 4-Diaminofuro [2,3-d] pyrimidines as Multi-receptor Tyrosine Kinase and Dihydrofolate Reductase Inhibitors with Antiangiogenic and Antitumor Activity. Bioorganic & Medicinal Chemistry 13:5475-5491.
  14. Gangjee, A., Jain, H.D., Kisliuk, R.L. 2005. Novel 2-Amino-4-oxo-5-arylthio-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. Bioorganic & Medicinal Chemistry Letters 15: 2225-2230.
  15. Gangjee, A., Vidwans, A., Elzein, E., McGuire, J. J., Queener, S. F., and Kisliuk, R. L. (2001). Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. J Med Chem 44, 1993-2003.
  16. Gangjee, A., Dubash, N.P., and Kisliuk, R.L. (2001). Synthesis of Novel, Nonclassical 2-amino-4-oxo-6(arylthio)ethylpyrrolo[2,3-d]pyrimidines as Potential Inhibitors of Thymidylate Synthase. J. Heterocyclic Chem. 38, 349-354.
  17. Gangjee, A., Yu, J., McGuire, J. J., Cody, V., Galitsky, N., Kisliuk, R. L., and Queener, S. F. (2000). Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent. J Med Chem 43, 3837-3851.
  18. Kisliuk, R. L. (2000). Synergistic interactions among antifolates. Pharmacol Ther 85, 183-190.
  19. Gangjee, A., Zeng, Y., McGuire, J. J., and Kisliuk, R. L. (2000). Effect of C9-methyl substitution and C8-C9 conformational restriction on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. J Med Chem 43, 3125-3133.
  20. Gangjee, A., Kothare, M., Kisliuk, R.L. (2000). The Synthesis of Novel Nonclassical Reversed bridge Quinazoline Antifolates as Inhibitors of Thymidylate Synthase. J. Heterocyclic Chem. 37, 1097-1102.
  21. Gangjee, A., Mavandadi, F., Kisliuk, R. L., and Queener, S. F. (1999). Synthesis of classical and a nonclassical 2-amino-4-oxo-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thymidylate synthase. J Med Chem 42, 2272-2279.
  22. Nair, M.G., Fayard, M.L., Lariccia, J.M., Amato, A.E., McGuire, J.J., Galivan, J.H., and Kisliuk, R.L. (1999). Metabolism Blocked Classical Folate Analogue Inhibitors of Dihydrofolate reductase-1: Synthesis and Biological Evaluation of Mobiletrex. Medicinal Chemistry Research 9, 176-185.
  23. Kisliuk, R.L. (1999). Folate Biochemistry in Relation to Antifolate Selectivity. In “Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy” (Jackman, A., ed.), Humana Press , Totowa, NJ, pp. 13-36.
  24. Gangjee, A., Vidwans, A. P., Vasudevan, A., Queener, S. F., Kisliuk, R. L., Cody, V., Li, R., Galitsky, N., Luft, J. R., and Pangborn, W. (1998). Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem 41, 3426-3434.
  25. Gangjee, A., Vasudevan, A., Queener, S. F., and Kisliuk, R. L. (1996). 2,4-diamino-5-deaza-6-substituted pyrido[2,3-d]pyrimidine antifolates as potent and selective nonclassical inhibitors of dihydrofolate reductases. J Med Chem 39, 1438-1446.
  26. Gangjee, A., Mavandadi, F., Kisliuk, R. L., McGuire, J. J., and Queener, S. F. (1996). 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. J Med Chem 39, 4563-4568.

             

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