Premium
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
Author(s) -
Birck Matthew R.,
Clinch Keith,
Gainsford Graeme J.,
Schramm Vern L.,
Tyler Peter C.
Publication year - 2009
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200900003
Subject(s) - chemistry , stereochemistry , phosphonate , pyrimidine , thymine , moiety , methyl group , glycogen phosphorylase , thymidine phosphorylase , group (periodic table) , dna , enzyme , organic chemistry , biochemistry
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.