title: Synthesis and anti-HIV activity of 2-, 3-, and 4-substituted analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
abstract: Several analogues of a new lead for anti-HIV-1 agents, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), in which the C-2, N-3, or C-4 position was modified were synthesized. These involve 2-thiothymine (11), 2-thiouracil (12), 4-thiothymine (17), 4-thiouracil (18), 5-methylcytosine (27), and cytosine (28) derivatives. Preparation of N-3-substituted derivatives (29 and 30) of HEPT was also carried out. Among these analogues, compound 11 exhibited excellent activity against HIV-1 HTLV-IIIB strain with an EC50 value of 0.98 microM, which is 7-fold more potent than that of HEPT. Removal of the 5-methyl group in compound 11 results in total loss of activity. Other compounds did not show any anti-HIV-1 activity. The 4-thio derivatives 17 and 18 were found to be rather cytotoxic. When compound 11 was evaluated for its inhibitory effects on another HIV-1 strain, HTLV-IIIRE, and two HIV-2 strains, LAV-2ROD and LAV-2EHO, it proved equally inhibitory to HTLV-IIIRF, whereas both HIV-2 strains were insensitive to the compound.
authors.affiliation: School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Ubasawa
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: K
authors.initials: K
authors.lastname: Sekiya
authors.forename: I
authors.initials: I
authors.lastname: Nitta
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: R T
authors.initials: RT
authors.lastname: Walker
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: T
authors.initials: T
authors.lastname: Miyasaka
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D013941:Thymine