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

Matthew R. Birck, Keith Clinch, Graeme J. Gainsford, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 N2 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 CH2 or CF2 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.

Original languageEnglish (US)
Pages (from-to)823-838
Number of pages16
JournalHelvetica Chimica Acta
Volume92
Issue number5
DOIs
StatePublished - May 2009

Fingerprint

Thymidine Phosphorylase
thymidine
Organophosphonates
Thymine
thymine
pyrimidines
Benzene
Phosphates
Cyclopentanes
Atoms
Pyrimidines
inhibitors
synthesis
products
phosphates
benzene
methylidyne
atoms
5-chlorouracil
pyrimidine

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Catalysis
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Inorganic Chemistry

Cite this

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. / Birck, Matthew R.; Clinch, Keith; Gainsford, Graeme J.; Schramm, Vern L.; Tyler, Peter C.

In: Helvetica Chimica Acta, Vol. 92, No. 5, 05.2009, p. 823-838.

Research output: Contribution to journalArticle

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