Phosphoramidate pronucleotides of cytostatic 6-aryl-7-deazapurine ribonucleosides |
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Authors: | Perlíková Pavla Pohl Radek Votruba Ivan Shih Robert Birkuš Gabriel Cihlář Tomáš Hocek Michal |
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Affiliation: | a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nám. 2, CZ-16610 Prague 6, Czech Republic b Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA |
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Abstract: | A series of O-phenyl methyl-, ethyl- and benzylalanyl phosphoramidate pronucleotides derived from cytostatic 6-aryl-7-deazapurine ribonucleosides were prepared by the cross-coupling reactions of the 2′,3′-isopropylidene protected 6-chloro-7-deazapurine ribonucleoside phosphoramidates with (het)arylboronic acids or -stannanes followed by deprotection. Most of the prepared prodrugs exerted in vitro cytostatic effects against both solid tumor and lymphoid cancer cells within low micromolar range of concentrations. These activities were in general weaker or comparable to the activities of the parent nucleosides. Additional testing of selected prodrugs suggests that the lack of activity improvement over parent nucleosides is not due to the lack of permeability or inefficient catabolism of alanyl-ester by intracellular hydrolases. More likely, active efflux of prodrugs may play a role in their weak cytotoxic activity. |
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Keywords: | Nucleosides Prodrugs ProTides Phosphoramidates Pyrrolo[2,3-d]pyrimidines |
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