Phosphoramidate pronucleotides of cytostatic 6-aryl-7-deazapurine ribonucleosides

0360990 - ÚOCHB 2012 RIV GB eng J - Journal Article
Perlíková, Pavla - Pohl, Radek - Votruba, Ivan - Shih, R. - Birkuš, G. - Cihlář, T. - Hocek, Michal
Phosphoramidate pronucleotides of cytostatic 6-aryl-7-deazapurine ribonucleosides.
Bioorganic & Medicinal Chemistry. Roč. 19, č. 1 (2011), s. 229-242. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA MŠMT 1M0508; GA ČR GAP207/11/0344
Institutional research plan: CEZ:AV0Z40550506
Keywords : nucleosides * prodrugs * proTides * phosphoramidates * pyrrolo[2,3-d]pyrimidines
Subject RIV: CC - Organic Chemistry
Impact factor: 2.921, year: 2011

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. However, active efflux of prodrugs may play a role in their weak cytotoxic activity.
Permanent Link: http://hdl.handle.net/11104/0198414