Masaru Ubasawa

Anti-human immunodeficiency virus type 1 activities and pharmacokinetics of novel 6-substituted acyclouridine derivatives.

The novel 6-substituted acyclouridine derivatives 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT), 1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenylthio)thymine (HEPT-M), 6-cyclohexylthio-1-[(2-hydroxyethoxy) methyl]thymine (HEPT-H), and 1-[(2-hydroxyethoxy)methyl]-6-phenylthio-2- thiothymine (HEPT-S) have proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell systems, including peripheral blood lymphocytes. They are not inhibitory to the replication of HIV-2. HEPT-S emerged as the most active congener, with a 50% inhibitory concentration of 1.6 microM for HIV-1 (human T-cell lymphotropic virus type IIIB) in MT-4 cells. We also examined the pharmacokinetics of the compounds following oral administration to rats. The pharmacokinetic profile varied considerably from one compound to another. The highest concentration in plasma (7.4 micrograms/ml, or 22.8 microM) was achieved by HEPT-S within 30 min after administration of an oral dose of 20 mg/kg of body weight. HEPT-S can be considered a promising candidate for the treatment of HIV-1 infections.

Molecular simulation of 5,6-substituted 1-[(2-hydroxyethoxy)methyl]uracils with anti-HIV-1 activity

Summary The dioxypyrimidine ring of 5,6-substituted 1-[(2-hydroxyethoxy)methyl]uracils is an extended ‘partial π system’ with ring distortion. PM3-MM+ geometry optimization suggested a lipophilic ‘butterfly-like’ orientation which was also found in other non-nucleoside inhibitors that interact with the HIV-1 reverse transcriptase. Multivariate QSAR has shown that discrimination between the antiviral response and undesired cytotoxicity is possible. Related to the C-6 thiophenyl ring substituents and to modifications at the C-5 position, the antiviral response depends on hydrogen-bonding forces, steric parameters, and electronic properties. The cytotoxicity depends on the lipophilicity and steric parameters.

Some Aspects on Acyclonucleoside Synthesis

Abstract An acyclonucleoside synthesis was investigated on the regioselective introduction of an acyclochain. We found that iodotrimethylsilane catalyzed the reaction of acyclochain introduction as well as its migration from S2 to N1 of 2-thiothymine and from N7 to N9 position of guanine. By taking the findings into account, several acyclo-nucleosides were synthesized in a simple one-pot procedure.