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Antimicrobial Agents and Chemotherapy, December 2002, p. 3854-3860, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3854-3860.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antiviral Activities and Cellular Toxicities of Modified 2',3'-Dideoxy-2',3'-Didehydrocytidine Analogues

Lieven J. Stuyver,1,2 Stefania Lostia,1 Marjorie Adams,1 Judy S. Mathew,1 Balakrishna S. Pai,1 Jason Grier,1 Phillip M. Tharnish,2 Yongseok Choi,3 Youhoon Chong,3 Hyunah Choo,3 Chung K. Chu,3 Michael J. Otto,2 and Raymond F. Schinazi1*

Veterans Affairs Medical Center and Department of Pediatrics, Emory University School of Medicine, Decatur, Georgia 30033,1 Pharmasset, Inc., Tucker, Georgia 30084,2 College of Pharmacy, University of Georgia, Athens, Georgia 306023

Received 16 April 2002/ Returned for modification 26 June 2002/ Accepted 27 August 2002

The antiviral efficacies and cytotoxicities of 2',3'- and 4'-substituted 2',3'-didehydro-2',3'-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC90s], 0.14 to 5.2 µM), but marked increases in EC90s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC90s, 53 to >100 µM). The ß-L-enantiomers of both classes of compounds were more potent than the corresponding ß-D-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC90, 0.25 µM). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 µM. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4'-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of ß-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC90, 0.08 µM) and lamivudine-resistant HIV-1 (EC90 = 0.15 µM) is markedly reduced by introduction of a 3'-fluorine in the sugar (EC90s of compound 2a, 37.5 and 494 µM, respectively).

* Corresponding author. Mailing address: Veterans Affairs Medical Center, Medical Research—151H, 1670 Clairmont Rd., Decatur, GA 30033. Phone: (404) 728-7711. Fax: (404) 728-7726. E-mail: rschina{at}emory.edu.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3854-3860, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3854-3860.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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