title: Stereoselective synthesis, chemistry and antiviral evaluation of 1-(2,3-dideoxy-3-C-hydroxymethyl-beta-D-threo-pentofuranosyl)thymine derivatives.
abstract: A series of novel 3'-C-branched 2',3'-dideoxynucleosides have been synthesized and evaluated as anti-HIV agents. Hydroboration of 2',3'-dideoxy-3'-C-methylene nucleoside proceeded regio- and stereoselectively to give 1-(2,3-dideoxy-3-C-hydroxy methyl-5-O-trityl-beta-D-threo-pentofuranosyl)thymine (5) after oxidation. 3'-C-Chloromethyl and 3'-C-iodomethyl 5'-O-protected 2',3'-dideoxynucleosides 9 and 12 were obtained from 5 by reaction with carbon tetrachloride/triphenylphosphine and methyltriphenoxyphosphonium iodide, respectively. Arbuzov reaction of 12 with triethyl phosphite afforded 3'-C-(diethyl-phosphono)methyl 5'-O-protected 2',3'-dideoxynucleoside 14. Compounds 5, 9, 12 and 14 were detritylated to give 1-(3-C-chloromethyl-2,3-dideoxy-beta-D-threo-pentofuranosyl)thymine (10), 1-(2,3-dideoxy-3-C-hydroxymethyl-beta-D-threo-pentofuranosyl)-thymine (11), 1-(2,3-dideoxy-3-C-iodomethyl-beta-D-threo-pentofuranosyl)thymine (13) and 1-(2,3-dideoxy-3-C-(O,O'-diethylphosphono)methyl-beta-D-threo- pentofuranosyl)thymine (15), respectively. These nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1) in vitro. Compound 5 demonstrated selective antiviral activity against HIV-1 but not HSV-1.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wengel
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: M H
authors.initials: MH
authors.lastname: Caruthers
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests; D013237:Stereoisomerism; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C097928:1-(2,3-dideoxy-3-C-hydroxymethyl-5-O-tritylpentofuranosyl)thymine; D000998:Antiviral Agents; D014320:Triphenylmethyl Compounds; D013941:Thymine