6-SUBSTITUTED 5-FLUOROURACIL DERIVATIVES AS TRANSITION STATE ANALOGUE INHIBITORS OF THYMIDINE PHOSPHORYLASE

@article{Kalman20056SUBSTITUTED5D,
  title={6-SUBSTITUTED 5-FLUOROURACIL DERIVATIVES AS TRANSITION STATE ANALOGUE INHIBITORS OF THYMIDINE PHOSPHORYLASE},
  author={Thomas I. Kalman and Li Lai},
  journal={Nucleosides, Nucleotides \& Nucleic Acids},
  year={2005},
  volume={24},
  pages={367 - 373}
}
  • T. Kalman, Li Lai
  • Published 1 April 2005
  • Chemistry, Biology
  • Nucleosides, Nucleotides & Nucleic Acids
A combination of mechanism-based and structure-based design strategies led to the synthesis of a series of 5- and 6-substituted uracil derivatives as potential inhibitors of thymidine phosphorlase/platelet derived endothelial cell growth factor (TP/PD-ECGF). Among those tested, 6-imidazolylmethyl-5-fluorouracil was found to be the most potent inhibitor with a Ki-value of 51 nM, representing a new class of 5-fluoropyrimidines with a novel mechanism of action. 
Kinetics and mechanistic study of competitive inhibition of thymidine phosphorylase by 5-fluoruracil derivatives.
Evolution of uracil based thymidine phosphorylase inhibitors, SAR and electronic correlation: revisit
TLDR
Uracil unit could be structurally modified at its N1, N3, C5, and C6 positions to afford innumerable uracil derivatives and substitution at 5‐ and 6‐positions have yielded fruitful results and excellent thymidine phosphorylase inhibitors prevailed.
Synthesis and in Vitro Evaluation of 5-Fluoro-6-[(2-Iminopyrrolidin-1-YL)Methyl]Uracil, TPI(F): An Inhibitor of Human Thymidine Phosphorylase (TP)
TLDR
The results indicate that further studies to develop 18F-labeled TPI(F) as a potential radiopharmaceutical for PET imaging of TP expression in vivo are warranted.
Efficient one-pot synthesis of polysubstituted 6-[(1 H -1,2,3-triazol-1-yl)methyl]uracils through the “click” protocol
The preparation of several triazolo acyclic nucleosides and triazolo acyclic nucleoside phosphonates is described. The synthetic methodology has been developed as an efficient one-pot Cu(I)-catalyzed
Preparation method of tipiracil intermediate
The invention provides a preparation method of a tipiracil intermediate which is 6-(chloromethyl)-2, 4-(1H, 3H)-pyrimidinedione. 6-methyl-2, 4-(1H, 3H)-pyrimidinedione as an initial raw material
Structural investigation of the thymidine phosphorylase from Salmonella typhimurium in the unliganded state and its complexes with thymidine and uridine.
TLDR
The various structural features of the enzyme which might be responsible for the specificity for thymidine and not for uridine were identified and the presence of the 2'-hydroxyl group in uridine results in a different position of the uridine furanose moiety compared with that of Thymidine, which may be the key element of the substrate specificity.
Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils and Their Transformation to 6-Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils, and 4,5,5-Trisubstit
TLDR
The electroreductive coupling of 1,3-dimethyluracil, thymine, and 5-fluorouracil with aromatic ketones in the presence of TMSCl gave 6-substituted and cis-5,6-disubstituting 5,6 -dihydro-1, 3-dim methyluracils, assigned by the coupling constants J5, 6 of their (1)H NMR spectra.
Stereoselective capture of N-acyliminium ions generated from α-hydroxy-N-acylcarbamides: direct synthesis of uracils from barbituric acids enabled by SmI2 reduction.
TLDR
The reaction involves the first generation of N-acyliminium ions directly from the versatile barbituric acids and proceeds with excellent stereoselectivity, thus providing a modular and highly practical sequence to the biologically significant uracil derivatives.
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The novel 5-halo-2-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP and may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.
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