title: Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products.
abstract: Reactions of O-t-butyldimethylsilyl-protected thymidine, 2'-deoxyuridine, and 3'-azidothymidine (AZT) with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) leads to activation of the C4 amide carbonyl by formation of putative O4-(benzotriazol-1-yl) derivatives. Subsequent substitution with alkyl and aryl amines, thiols, and alcohols leads to facile functionalization at this position. Reactions with amines and thiols were conducted either as a two-step, one-pot transformation, or as a one-step conversion. Reactions with alcohols were conducted as two-step, one-pot transformations. In the course of these investigations, the formation of 1-(4-pyrimidinyl)-1H-benzotriazole-3-oxide derivatives from the pyrimidine nucleosides was identified. However, these too underwent conversion to the desired products. Products obtained from AZT were converted to the 3'-amino derivatives by catalytic reduction. All products were assayed for their abilities to inhibit cancer cell proliferation and for antiviral activities. Many were seen to be active against HIV-1 and HIV-2, and one was active against herpes simplex virus-1 (HSV-1).
authors.affiliation: Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031, USA. mlakshman@ccny.cuny.edu and The Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, USA.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Akula
authors.affiliation: Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031, USA. mlakshman@ccny.cuny.edu.
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Kokatla
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, 3000 Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, 3000 Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, 3000 Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031, USA. mlakshman@ccny.cuny.edu.
authors.forename: Lijia
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Biochemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031, USA. mlakshman@ccny.cuny.edu and The Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, USA.
authors.forename: Mahesh K
authors.identifier: http://orcid.org/0000-0002-9555-027X
authors.initials: MK
authors.lastname: Lakshman
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000821:virology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000626491:(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; D000577:Amides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D011741:Pyrimidine Nucleosides