Portal de Periódicos da CAPES

Synthesis and Antiviral Activity of Some 2-Substituted 3-Formyl-and 3-Cyano-5,6-Dichloroindole Nucleosides

2005; Taylor & Francis; Volume: 24; Issue: 10-12 Linguagem: Inglês

10.1080/15257770500265836

1532-2335

John D. Williams, John C. Drach, Leroy B. Townsend,

Cytomegalovirus and herpesvirus research

A series of dichlorinated 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 isopropylidene-protected analogs of the previously reported 3-formyl-2,5,6-trichloro-1-(β-D-ribofuranosyl)indole (FTCRI) and 3-cyano-2,5,6-trichloro-1-(β-D-ribofuranosyl)indole (CTCRI) were modified by nucleophilic displacement of the 2-chloro substituent using secondary amines. Deprotection of the intermediates provided 2-substituted analogs of FTCRI and CTCRI in good yield. There was a significant difference in reactivity between the isopropylidene-protected and the fully deprotected FTCRI and CTCRI with respect to nucleophilic displacement of the 2-chloro substituent using dialkylamines. This difference in reactivity was not observed with monoalkylamines or with alkoxides, and the corresponding 2-alkylamino- and 2-methoxy substituted analogs were synthesized from FTCRI and CTCRI directly. None of the synthesized analogs demonstrated potent antiviral activity without some corresponding cytotoxicity. Keywords: Indole nucleosideNucleoside analogTCRBAntiviralHuman cytomegalovirus (HCMV) This manuscript is dedicated to the memory of Dr. John A. Montgomery. We thank Julie M. Breitenbach and Kathy Z. Borysko for expert performance of antiviral and cytotoxicity assays. These studies were supported by training grant T32-GM07767 and research grants U19-AI31718 and P01-AI46390 from the National Institutes of Health. Notes a Plaque reduction assays were performed in duplicate wells as described in the text. b Compounds were assayed by ELISA in quadruplicate wells. c Visual cytotoxicity was scored on HFF cells at the time of HCMV plaque enumeration in duplicate wells; inhibition of KB cell growth was determined in triplicate wells as described in the text. d > 100 indicates an IC50 greater than the highest concentration tested. e Data for compounds 2 and 3 published previously as compounds 9a and 9b, respectively, in Williams et al.[Citation11] f Data for TCRB published previously as compound 9 in Townsend et al.[Citation9] g Averages from 108, 33, and 3 experiments, respectively, using ganciclovir (GCV).