Novel nonsubstrate inhibitors of human thymidine phosphorylase, a potential target for tumor-dependent angiogenesis.
Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is an enzyme involved in thymidine metabolism and homeostasis, and its catalytic activity appears to play an important role in angiogenesis. Here we describe the cloning and expression of a His-tagged human TP/PD-ECGF and its assay with uracil and thymine analogues. We present the design, synthesis, and biological evaluation of novel 6-(phenylalkylamino)uracil derivatives which, at micromolar concentrations, inhibit both catabolic and anabolic reactions of human TP in vitro. These base analogues are not converted by the enzyme into the nucleoside form, thus representing pure nonsubstrate inhibitors of the enzyme.
Focher
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F
Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia, Italy. r@igbe.pv.cnr.it
Ubiali
D
D
Pregnolato
M
M
Zhi
C
C
Gambino
J
J
Wright
G E
GE
Spadari
S
S
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001792:Blood Platelets / Q000737:chemistry; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014498:Uracil; D013939:Thymidine Phosphorylase