Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Journal of Medicinal Chemistry

Volumn 40, Issue 12, 1997, Pages 1845-1854

  Pontikis, Renée ^a   Benhida, Rachid ^a   Aubertin, Anne Marie ^c   Grierson, David S ^b   Monneret, Claude ^a  

^a CNRS   (France)

^b INSTITUT DE CHIMIE DES SUBSTANCES NATURELLES   (France)

^c UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(2 HYDROXYETHOXY)METHYL] 6 (PHENYLTHIO)THYMINE; THYMINE DERIVATIVE;

ACYLATION; ANTIVIRAL ACTIVITY; ARTICLE; CHEMICAL MODIFICATION; DRUG SYNTHESIS; ENZYME INHIBITION; GENETIC ANALYSIS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MOLECULAR MODEL; NONHUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; VIROGENESIS; VIRUS INHIBITION;

EID: 0030994577     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960765a     Document Type: Article

References (53)

1. Barre-Sinoussi, F.; Chermann, J. C.; Rey, F.; Nugeyre, M. T.; Chamaret, S.; Gruest, J.; Dauguet, C.; Axler-Blin, C.; Vezinet-Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS). Science 1983, 220, 868-871.
2. Gallo, R. C.; Salahuddin, S. Z.; Popovic, M.; Shearer, G. M.; Kaplan, M.; Haynes, B. F.; Palker, T. J.; Redfield, R.; Oleske, J.; Safai, B.; White, G.; Foster, P.; Markham, P. D. Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS. Science 1984, 224, 500-503.
3. Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottlieb, M. S.; Volberding, P. A.; Laskin, O. L.; Leedom, J. M.; Groopman, J. E.; Mildvan, D.; Schooley, R. T.; Jackson, G. G.; Durack, D. T.; King, D.; the AZT Collaborative Working Group. The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-related Complex. A Double-Blind Placebo-Controlled Trial. N. Engl. J. Med. 1987, 317, 185-191.
4. Mitsuya, H.; Broder, S. Inhibition of the in vitro Infectivity and Cytopathic Effect of Human T-Lymphotropic Virus Type III/ Lymphadenopathy-Associated Virus (HTLV-III/LAV) by 2′,3′-Dideoxynucleosides. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911-1915.
5. Yarchoan, R.; Mitsuya, H.; Thomas, R. V.; Pluda, J. M.; Hartmann, N. R.; Perno, C.-F.; Marczyk, K. S.; Allain, J. P.; Johns, D. G.; Broder, S. In vivo Activity against HIV and Favorable Toxicity Profile of 2′,3′-Dideoxyinosine. Science 1989, 245, 412-415.
6. Richman, D. D. Resistance of Clinical Isolates of Human Immuno-deficiency Virus to Antiretroviral Agents. Antimicrob. Agents Chemother. 1993, 37, 1207-1213.
7. De Clercq, E. HIV Resistance to Reverse Transcriptase Inhibitors. Biochem. Pharmacol. 1994, 47, 155-169.
8. Tantillo, C.; Ding, J.; Jacobo-Molina, A.; Nanni, R. G.; Boyer, P. L.; Hughes, S. H.; Pauwels, R.; Andries, K.; Janssen, P. A.; Arnold, E. Location of Anti-AIDS Drug Binding Sites and Resistance Mutations in the Three-dimensional Structure of HIV-1 Reverse Transcriptase. Implications for Mechanisms of Drug Inhibition and Resistance. J. Mol. Biol. 1994, 243, 369-387.
9. Romero, D. L. Advances in the Development of HIV Reserve Transcriptase Inhibitors. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, CA, 1994; Vol. 29, pp 123-132.
10. Smerdon, S. J.; Jäger, J.; Wang, J.; Kohlstaedt, L. A.; Chirino, A. J.; Friedman, J. M.; Rice, P. A.; Steitz, T. A. Structure of the binding site for nonnucleoside inhibitors of the reserve transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3911-3915.
11. Spence, R. A.; Kati, W. M.; Anderson, K. S.; Johnson, K. A. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Nonnucleoside Inhibitors. Science 1995, 267, 988-993.
12. Ding, J.; Das, K.; Moereels, H.; Koymans, L.; Andries, K.; Janssen, P. A. J.; Hughes, S. H.; Arnold, E. Structure of HIV-1 RT/TIBO R86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat. Struct. Biol. 1995, 2, 407-415 and references cited therein.
13. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. High resolution structures of HIV-1 RT from four RT-inhibitors complexes. Nat. Struct. Biol. 1995, 2, 293-302.
14. Johnson, V. A. Combination Therapy: More Effective Control of HIV Type 1? AIDS Res. Hum. Retroviruses 1994, 10, 907-912.
15. De Jong, M. D.; Boucher, C. A. B.; Galasso, G. J.; Hirsh, M. S.; Kern, E. R.; Lange, J. M. A.; Richman, D. D. Consensus symposium on combinated antiviral therapy. Antiviral Res. 1995, 29, 5-29.
16. Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker, R. T.; Balzarini, J.; De Clercq E. A Novel Lead for Specific Anti-HIV-1 Agents: 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine. J. Med. Chem. 1989, 32, 2507-2509.
17. Mellors, J. W.; Im, G.-J., Tramontano, E.; Winkler, S. R.; Medina, D. J.; Dutschman, G. E.; Bazmi, H. Z.; Piras, G.; Gonzalez, C. J.; Cheng, Y.-C. A Single Conservative Amino Acid Substitution in the Reverse Transcriptase of Human Immunodeficiency Virus-1 Confers Resistance to (+)-(5S)-4,5,6,7-Tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1, 4]benzodiazepin-2(1H)-thione (TIBO R82150). Mol. Pharmacol. 1993, 43, 11-16.
18. Balzarini, J.; Karlsson, A.; De Clercq, E. Human Immunodeficiency Virus Type 1 Drug-Resistance Patterns with Different [1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine Derivatives. Mol. Pharmacol. 1993, 44, 694-701.
19. Tanaka, H.; Baba, M.; Saito, S.; Miyasaka, T.; Takashima, H.; Sekiya, K.; Ubazawa, M.; Nitta, I.; Walker, R. T.; Nakashima, H.; De Clercq, E. Specific anti-HIV-1 "Acyclonucleosides" Which Cannot be Phosphorylated: Synthesis of Some Deoxy Analogues of [1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thvmine. J. Med. Chem. 1991, 34, 1508-1511.
20. Tanaka, H.; Takashima, H.; Ubazawa, M.; Sekiya, K.; Inouye, N.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. Synthesis and Antiviral Activity of 6-Benzyl Analogs of [1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as Potent and Selective Anti-HIV-1 Agents. J. Med. Chem. 1995, 38, 2860-2865 and references cited therein.
21. De Clercq, E. HIV-1-Specific RT Inhibitors. Highly Selective Inhibitors of Human Immunodeficiency Virus Type 1 That Are Specifically Targeted at the Viral Reverse Transcriptase. Med. Res. Rev. 1993, 13, 229-258.
22. Fossey, C.; Laduree, D.; Robba, M. Synthesis of Acyclic Thieno[3,2-d]pyrimidine Nucleosides and Azido-derivatives as Potential Anti-HIV Agents. Nucleosides Nucleotides 1994, 13, 883-889.
23. Pan, B.-C.; Chen, Z.-H.; Piras, G.; Dutschman, G. E.; Rowe, E. C.; Cheng, Y.-C.; Chu, S.-H. Synthesis and Anti-HIV-l Activities of 6-Arylthio and 6-Arylselenoacyclonucleosides. J. Heterocycl. Chem. 1994, 31, 177-185.
24. Maruenda, H.; Johnson, F. Design and Synthesis of Novel Inhibitors of HIV-1 Reverse Transcriptase. J. Med. Chem. 1995, 38, 2145-2151.
25. Danel, K.; Larsen, E.; Pedersen, E. B.; Vestergaard, B. F.; Nielsen, C. Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of [1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine. J. Med. Chem. 1996, 39, 2427-2431.
26. 19 by introduction of the thiophenyl group at the C-6 position of appropriate acyclothymidine derivatives.
27. Nakagawa, I.; Aki, K.; Hata, T. Synthesis of 5′-Alkylthio-5′-deoxynucleosides from Nucleosides in a One-pot Reaction. J. Chem. Soc., Perkin Trans. I 1983, 1315-1318.
28. Buckheit, R. W.; Fliakas-Boltz, V.; Yeagy-Bargo, S.; Weislow, O.; Mayers, D. L.; Boyer, P. L.; Hughes, S. H.; Pan, B.-C.; Chu, S.-H.; Bader, J. P. Resistance to 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine Derivatives is Generated by Mutations at Multiple Sites in the HIV-1 Reverse Transcriptase. Virology 1995, 210, 186-198.
29. Soai, K.; Yokoyama, S.; Mochida, K. Reduction of Symmetric and Mixed Anhydrides of Carboxylic Acids by Sodium Borohydride with Dropwise Addition of Methanol. Synthesis 1987, 647-648.
30. 31
31. Iwasaki, M.; Kobayashi, Y.; Li, J.-P.; Matsuzaka, H.; Ishii, Y.; Hidai, M. Palladium-Catalyzed Cyclocarbonylation of 3-(Heteroaryl)allyl Acetates. J. Org. Chem. 1991, 56, 1922-1927.
32. Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Nitta, I.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. Synthesis and Antiviral Activity of Deoxy Analogs of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as Potent and Selective Anti-HIV-1 Agents. J. Med. Chem. 1992, 35, 4713-4719.
33. Kundu, N. G.; Hertzberg, R. P.; Hannon, S. J. Removal of N-Benzyl-and N-Benzyloxymethyl Substituents from Substituted Uracils with Boron Tribromide. Tetrahedron Lett. 1980, 21, 1109-1112.
34. Saneyoshi, M.; Watanabe, S. Synthetic Nucleosides and Nucleotides. XXVIII. Synthesis of 5-Alkylcytidines from 5-Alkylbarbituric Acids. Chem. Pharm. Bull. 1988, 36, 2673-2678.
35. Kundu, N. G.; Das, B.; Spears, C. P.; Majumdar, A.; Kang, S.-I. Synthesis and Biological Activities of Novel 5-(2-Acylethynyl)-uracils. J. Med. Chem. 1990, 33, 1975-1979.
36. Pontikis, R.; Monneret, C. Synthesis of Deoxy Analogs of HEPT involving a Palladium(0) Catalyzed Coupling. Tetrahedron Lett. 1994, 35, 4351-4354.
37. 2O, 60 °C].
38. Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. Palladium-Catalyzed Allylation of Pyrimidine-2,4-diones (Uracils) and of 6-Membered Heterocyclic Ambident Sulfur Nucleophiles. Tetrahedron 1993, 49, 1457-1464.
39. Sigismondi, S.; Sinou, D.; Pérez, M.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. Palladium(0)-Catalyzed Allylation of Uracils and 2-Thiouracils. Drastic Effect of an Aqueous Reaction Medium on the Regioselectivity. Tetrahedron Lett. 1994, 35, 7085-7088.
40. Shugar, D.; Fox, J. J. Spectrophotometric studies of Nucleic Acid Derivatives and Related Compounds as a Function of pH. I. Pyrimidines. Biochim. Biophys. Acta 1952, 9, 199-218.
41. Shapiro, R.; Kang, S. Buffer-Catalyzed Tautomerism of Uracil Monoanion. Biochim. Biophys. Acta 1971, 232, 1-4.
42. 3 of the N-1,3-bis-alkylated intermediate.
43. 19 with chloro and fluoro analogs in MT-4 cells.
44. Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Nitta, I.; Baba, M.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. Structure-Activity Relationships of 1-[(2-Hydroxyethoxy)-methyl]-6-(phenylthio)thymine analogues: Effect of Substitutions at the C-6 Phenyl ring and at the C-5 Position on Anti-HIV-1 Activity. J. Med. Chem. 1992, 35, 337-345.
45. Tanaka, H.; Baba, M.; Ubasawa, M.; Takashima, H.; Sekiya, K.; Nitta, I.; Shigeta, S.; Walker, R. T.; De Clercq, E.; Miyasaka, T. Synthesis and Anti-HIV Activity of 2-, 3-, and 4-Substituted Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J. Med. Chem. 1991, 34, 1394-1399.
46. Hopkins, A. L.; Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross, C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers, D. K.; Stuart, D. I. Complexes of HIV-1 Reverse Trancriptase with Inhibitors of the HEPT Series Reveal Conformational Changes Relevant to the Design of Potent Non-Nucleoside Inhibitors. J. Med. Chem. 1996, 39, 1589-1600.
47. 46 This analysis reveals the functional roles of each substituent, including that of the terminal phenyl ring, regarding the position of the inhibitor within the hydrophobic pocket.
48. Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.; Miyasaka T.; Ubasawa, M.; Takashima, H.; Sekiya, K.; Nitta, I.; Shigeta, S.; Walker, R. T.; Balzarini, J., De Clercq, E. A New Class of HIV-1-Specific 6-Substituted Acyclouridine Derivatives: Synthesis and Anti-HIV Activity of 5-or 6-Substituted Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J. Med. Chem. 1991, 34, 349-357.
49. Dauzonne, D.; Gillardin, J. M.; Lepage, F.; Pointet, R.; Rissé, S.; Lamotte, G.; Demerseman, P. Synthesis and some CNS activities of new benzofuranylacryloylpíperazines. Eur. J. Med. Chem. 1995, 30, 53-59.
50. Shapira, J. Synthesis of 5-Ethyluridine, a Model 5-Alkyl Substituted Pyrimidine Nucleoside. J. Org. Chem. 1962, 27, 1918-1919.
51. Moog, C.; Wick, A.; Le Ber, P.; Kirn, A.; Aubertin, A.-M. Bicyclic imidazo derivatives, a new class of highly selective inhibitors for the human immunodeficientcy virus type 1. Antiviral Res, 1994, 24, 275-288.
52. 50, synergism, antagonism, low-dose risk, receptor binding and enzyme kinetics. Computer software for Apple II series and IBM-PC and instruction manual; Elsevier-Biosoft, Elsevier Science Publishers: Cambridge, U.K., 1985; pp 19-28.
53. Mosmann, T. Rapid colorimetic assay for cellular growth and survival: application to proliferation and cytotoxic assays. J Immunol. Methods 1983, 65, 55-63.