title: Synthesis, antiviral activity, and mode of action of some 3-substituted 2,5,6-trichloroindole 2'- and 5'-deoxyribonucleosides.
abstract: A series of chlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The 2'- and 5'-deoxy derivatives of the reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and 3-cyano-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (CTCRI) were synthesized by either a modification of the appropriate 3-unsubstituted sugar-modified nucleoside analogues or by a glycosylation of 3-substituted heterocycles with a protected alpha-chlorosugar. The modifications were guided in part by structural similarity to the corresponding series of chlorinated benzimidazole ribonucleosides and the fact that 5'-deoxy analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) are very active against HCMV. The 5'-deoxy analogues of FTCRI and CTCRI were nearly as active as FTCRI and CTCRI, suggesting that the chlorinated benzimidazole nucleosides and the chlorinated indole nucleosides act in a similar manner. This hypothesis was supported by time-of-addition studies using FTCRI and by the resistance of TCRB-resistant strains of HCMV to four different 3-substituted indole ribonucleosides. The 2'-deoxy analogues of the trichlorinated indole nucleosides also had potent antiviral activity, in contrast to decreased activity and selectivity observed for 2'-deoxy TCRB compared to TCRB. In addition, 3-acetyl-2,5,6-trichloro-1-(2-deoxy-beta-d-ribofuranosyl)indole was also active and much less cytotoxic (HCMV IC50 = 0.30 microM, HFF CC50 >100 microM) than previous analogues. None of the analogues had significant activity against HSV-1.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48019, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Leroy B
authors.initials: LB
authors.lastname: Townsend
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D003853:Deoxyribonucleosides; D007211:Indoles