Syntheses of 5-Chlorouracils/Thymines with 1-[Phosphono(Methyl/Difluoromethyl)]-1,2-Unsaturated-Moiety-Substituted Methyl Groups at N(1) and Human Thymidine Phosphorylase Inhibitory Activity
✍ Scribed by Matthew R. Birck; Keith Clinch; Graeme J. Gainsford; Vern L. Schramm; Peter C. Tyler
- Book ID
- 102260229
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- German
- Weight
- 269 KB
- Volume
- 92
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
Abstract
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By attaching (methyl)‐ or (difluoromethyl)‐phosphonate groups to the 1‐positions of ethene, cyclopentene or benzene, and attaching 1‐(methyl)‐5‐chlorouracil or 1‐(methyl)thymine groups to the corresponding 2‐positions, compounds 1–5 were prepared as potential inhibitors of recombinant human thymidine phosphorylase (TP). The products were designed to mimic the interatomic distance (ca. 3.41 Å) between the incoming phosphate and leaving pyrimidine groups at the transition state for the putative S~N~2 mechanism of TP. Free rotation around the (unsaturated‐CH~2~)–pyrimidine bonds in 1–5 enabled a span of ca. 2.40–4.40 Å between the CH~2~ or CF~2~ C‐atoms in the phosphonates and N(1) of the pyrimidines to be covered. The products were found to be ineffective inhibitors, and some reasons for this are given.