Potential anti-AIDS drugs. 2',3'-Dideoxycytidine analogs

5-Substituted 2',3'-dideoxycytidine analogues have been synthesized and evaluated in vitro for their capabilities to protect T4+ lymphocytes from the cytopathic effects of the HTLV-III/LAV (HIV) virus, the causative agent of acquired immunodeficiency syndrome (AIDS). These analogues were d...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-05, Vol.30 (5), p.862-866
Main Authors: Kim, Chong Ho, Marquez, Victor E, Broder, Samuel, Mitsuya, Hiroaki, Driscoll, John S
Format: Article
Language:English
Subjects:
Acquired Immunodeficiency Syndrome - drug therapy
Carbohydrates. Nucleosides and nucleotides
Cell Line
Chemical Phenomena
Chemistry
Deoxycytidine - analogs & derivatives
Deoxycytidine - chemical synthesis
Deoxycytidine - pharmacology
Deoxycytidine - therapeutic use
Exact sciences and technology
HIV - drug effects
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Preparations and properties
Structure-Activity Relationship
T-Lymphocytes, Helper-Inducer - microbiology
Zalcitabine
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Summary:5-Substituted 2',3'-dideoxycytidine analogues have been synthesized and evaluated in vitro for their capabilities to protect T4+ lymphocytes from the cytopathic effects of the HTLV-III/LAV (HIV) virus, the causative agent of acquired immunodeficiency syndrome (AIDS). These analogues were designed to be more lipophilic than 2',3'-dideoxycytidine (ddC) in order to enhance central nervous system penetration. Earlier reports had shown that ddC is a potent protective agent. When ddC is substituted at the 5-position with either methyl or bromo substituents, activity is completely abolished. However, when the substitution is fluoro (5-F-ddC), both activity and potency are retained. 2',3'-Dideoxy-5-azacytidine is also protective but more toxic than ddC or 5-F-ddC. In a different approach, an attempt was made to utilize ddCMP, ddTMP, and ddAMP as preformed nucleotides in order to circumvent the generally low level of phosphorylation achieved with dideoxynucleosides which function as relatively poor substrates for the cellular kinases. Only ddAMP is as active as its nucleoside precursor. Because ddAMP is not more active than ddA at low concentrations, it is possible that the active agent is ddA which is generated from ddAMP prior to cell entry.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00388a020