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1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes. 1993

H O Kim, and R F Schinazi, and S Nampalli, and K Shanmuganathan, and D L Cannon, and A J Alves, and L S Jeong, and J W Beach, and C K Chu
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602.

In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV-1 agents, various enantiomers of pure dioxolanylpurine nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 1, which was synthesized in nine steps from 1,6-anhydro-beta-D-mannose, was condensed with 6-chloropurine, 6-chloro-2-fluoropurine, and 2,6-dichloropurine in the presence of TMS triflate. The chloro or fluoro substituents were readily converted into amino, N-methylamino, hydroxy, methoxy, thiol, and methylthio under appropriate reaction conditions. Upon evaluation of these dioxolanes, the guanine derivative 24 exhibited the most potent anti-HIV-1 activity without cytotoxicity up to 100 microM in various cells. The decreasing antiviral activity order of beta-isomers was as follows: guanine > 6-chloro-2-aminopurine > 2-fluoroadenine > or = adenine > or = 2,6-diaminopurine > hypoxanthine > 2-chloroadenine > 6-chloropurine approximately equal to N6-methyladenine approximately equal to 6-mercaptopurine approximately equal to 6-(methylthio)purine.

UI MeSH Term Description Entries
D008214 Lymphocytes White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each), or NATURAL KILLER CELLS. Lymphoid Cells,Cell, Lymphoid,Cells, Lymphoid,Lymphocyte,Lymphoid Cell
D009705 Nucleosides Purine or pyrimidine bases attached to a ribose or deoxyribose. (From King & Stansfield, A Dictionary of Genetics, 4th ed) Nucleoside,Nucleoside Analog,Nucleoside Analogs,Analog, Nucleoside,Analogs, Nucleoside
D004148 Dioxolanes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human

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