Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs.
Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2'-aminoimidazol-1'-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC(50) values of approximately 20 nM when the enzyme concentration is approximately 40 nM. Their 4'-aminoimidazol-1'-yl analogues (4, X = Cl, Br) are >350-fold less active with IC(50) values of approximately 7 microM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pK(a) values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2'-nitroimidazol-1'-ylmethyluracils (5, X = Cl, Br) are >1000-fold less active (IC(50) 22-24 microM) than their 2'-amino analogues and are reduced to the 2'-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2'-nitro prodrugs have the potential to selectively deliver the potent 2'-aminoimidazol-1'-yl TP inhibitors into hypoxic solid tumors.
Reigan
Philip
P
School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Edwards
Philip N
PN
Gbaj
Abdul
A
Cole
Christian
C
Barry
Simon T
ST
Page
Ken M
KM
Ashton
Susan E
SE
Luke
Richard W A
RW
Douglas
Kenneth T
KT
Stratford
Ian J
IJ
Jaffar
Mohammed
M
Bryce
Richard A
RA
Freeman
Sally
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D004926:Escherichia coli / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007093:Imidazoles; D009593:Nitroimidazoles; D011355:Prodrugs; D014498:Uracil; D013939:Thymidine Phosphorylase