Synthesis of an Epoxide Derivative of Thymidine as a Potential Enzyme Inhibitor |
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Authors: | H. Jeanette Thomas Robert D. Elliott James M. Riordan John A. Montgomery |
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Affiliation: | Kettering-Meyer Laboratory, Southern Research Institute , P. O. Box 55305, Birmingham, Alabama , 35255-5305 |
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Abstract: | Abstract Attempts to prepare I -[7,8-anhydro-2,5,6-trideoxy-α-L-lyxo-(and β-n-ribo)-octofuranosyl]thymine (10) by treatment of halohydrins 6–9 with sodium hydride in DMF or sodium methoxide in methanol gave mixtures of the epoxides 10 or 11 and the 3′,8′-anhydronucleoside 12. The structure of 12 was confirmed by oxidation to the cyclic ketone 14. The successful synthesis of 10 involved a Wittig reaction on the thymidine-5′-aldehyde 16 to give the unsaturated ketoacetate 18 which was reduced in two steps to the diacetate 20. The 7′-O-tosyl derivative 21 upon treatment with sodium methoxide in chloroform gave the pure epoxide 10 which was marginally toxic to L1210 cells in culture (I50=25 μM) and demonstrated borderline in vivo activity (24% ILS) against P388 murine leukemia. |
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Keywords: | Antiviral agents Branched nucleoside Apiosyl nucleoside Claisen rearrangement Ozonolysis |
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