β-&lt;i&gt;L&lt;/i&gt;-1,3-Dioxolane-Cytidine:A Novel Nucleoside ThatInhibits Proliferation andInduces Differentiation ofKeratinocytes in vitro

Schwartz, Pauline M.; Haggerty, John G.; Cheng, Yung‐Chi

doi:10.1159/000029829

Cited by 7 publications

(2 citation statements)

References 15 publications

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“…In fact, the L-isomer of dioxalanecytidine triphosphate (LOddCTP) is actually a better inhibitor than its enantiomeric AS Ray et al 120 ©2003 International Medical Press Ray et al, 2002a. Image generated from the crystal structure of the ternary complex of HIV-1 RT, primer/template and TTP (Huang et al, 1998) partner for some human DNA polymerases (Kukhanova et al, 1995;Grove & Cheng, 1996) and L-OddC (Troxatyl TM , Shire Pharmaceuticals Plc.) is currently being developed as an anticancer agent (Schwartz et al, 1998).…”

Section: Structural Implications For the Kinetic Datamentioning

confidence: 99%

“…Nitrogen (blue), carbon (white), oxygen (red) and phosphorus or sulphur (yellow) are displayed for TTP and the active site residues Arg 72, Tyr 115, Met 184 and Gln 151. partner for some human DNA polymerases (Kukhanova et al, 1995;Grove & Cheng, 1996) and L-OddC (Troxatyl TM , Shire Pharmaceuticals Plc.) is currently being developed as an anticancer agent (Schwartz et al, 1998). Certain modifications may have differential effects depending on the enantiomer.…”

Section: Structural Implications For the Kinetic Datamentioning

confidence: 99%

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Probing the Mechanistic Consequences of 5-Fluorine Substitution on Cytidine Nucleotide Analogue Incorporation by HIV-1 Reverse Transcriptase

Ray

Schinazi

Murakami

et al. 2003

Antivir Chem Chemother

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β-D and β-L-enantiomers of 2′,3′-dideoxycytidine analogues are potent chain-terminators and antimetabolites for viral and cellular replication. Seemingly small modifications markedly alter their antiviral and toxicity patterns. This review discusses previously published and recently obtained data on the effects of 5- and 2′-fluorine substitution on the pre-steady state incorporation of 2′-deoxycytidine-5′-monophosphate analogues by HIV-1 reverse transcriptase (RT) in light of their biological activity. The addition of fluorine at the 5-position of the pyrimidine ring altered the kinetic parameters for all nucleotides tested. Only the 5-fluorine substitution of the clinically relevant nucleosides (-)-β-L-2′,3′-dideoxy-3′-thia-5-fluoro-cytidine (L-FTC, Emtriva™), and (+)-β-D-2′,3′-dide-hydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC, Reverset™), caused a higher overall efficiency of nucleotide incorporation during both DNA- and RNA-directed synthesis. Enhanced incorporation by RT may in part explain the potency of these nucleosides against HIV-1. In other cases, a lack of correlation between RT incorporation in enzymatic assays and antiviral activity in cell culture illustrates the importance of other cellular factors in defining antiviral potency. The substitution of fluorine at the 2′ position of the deoxyribose ring negatively affects incorporation by RT indicating the steric gate of RT can detect electrostatic perturbations. Intriguing results pertaining to drug resistance have led to a better understanding of HIV-1 RT resistance mechanisms. These insights serve as a basis for understanding the mechanism of action for nucleoside analogues and, coupled with studies on other key enzymes, may lead to the more effective use of fluorine to enhance the potency and selectivity of antiviral agents.

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