Synthesis of two cyclopentenyl-3-deazapyrimidine carbocyclic nucleosides related to cytidine and uridine.
The cytosine analogue of neplanocin A, cyclopentenylcytosine (CPE-C, 3), has significant antitumor and antiviral activity commensurate with the drug's ability to produce a significant depletion of cytidine triphosphate (CTP) levels that result from the potent inhibition of cytidine triphosphate synthetase. Another important antitumor agent, previously identified as a potent inhibitor of the same enzyme, is 3-deazauridine (2). The synthesis of the cyclopentenyl nucleosides 3-deaza-CPE-C (5) and 3-deaza-CPE-U (6) was undertaken in order to investigate the effects of a modified 3-deaza pyrimidine aglycon moiety on the biological activity of the parent CPE-C. These compounds were synthesized via an SN2 displacement reaction on cyclopenten-1-ol methanesulfonate (10) by the sodium salt of the corresponding aglycon. In each case, separation and characterization of the corresponding N- and O-alkylated products was necessary before final removal of the blocking groups. The target compounds were devoid of in vitro antiviral activity against the HSV-1 and human influenza viruses. Although 3-deaza-CPE-C was nontoxic to L1210 cells in culture, 3-deaza-CPE-U displayed significant cytotoxicity against murine L1210 leukemia in vitro.
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Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Marquez
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D015092:3-Deazauridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007202:Indicators and Reagents; D007939:Leukemia L1210; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D007202:Indicators and Reagents; C067175:cyclopentenyl-3-deazacytidine; C067176:3-deazacyclopentenylcytosine; D015092:3-Deazauridine; D003562:Cytidine; D014529:Uridine