title: Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase.
abstract: A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.
authors.affiliation: Attenuon, LLC, 11535 Sorrento Valley Road Suite 401, San Diego, CA 92121, USA. allan@attenuon.com
authors.forename: Amy L
authors.initials: AL
authors.lastname: Allan
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Gladstone
authors.forename: Melissa L P
authors.initials: ML
authors.lastname: Price
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Hopkins
authors.forename: Jose C
authors.initials: JC
authors.lastname: Juarez
authors.forename: Fernando
authors.initials: F
authors.lastname: Doñate
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ternansky
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.forename: Bruce
authors.initials: B
authors.lastname: Ganem
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Li
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Ealick
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; D013939:Thymidine Phosphorylase