An investigation of the kinetic and anti-angiogenic properties of plant glycoside inhibitors of thymidine phosphorylase.
We investigated the potential of symplocomoside (1) and symponoside (2), glycosides isolated from the bark of Symplocos racemosa to inhibit thymidine phosphorylase (TP) activity and associated angiogenesis. Compound 1 was a reversible, noncompetitive inhibitor of deoxythymidine binding to TP (IC(50) = 65.45 +/- 5.08 microM; K(i) = 62.83 +/- 2.10 microM) and 2 was a reversible, uncompetitive inhibitor (IC(50) = 94.17 +/- 4.05 microM; K(i) = 101.95 +/- 1.65 microM). Molecular modeling analysis indicated that both compounds bound at the active site of the enzyme but not solely to amino acid residues involved in catalysis. Both compounds were active in in vitro angiogenic assays inhibiting endothelial cell migration and invasion in Matrigel, but did not inhibit growth factor-induced proliferation and were not cytotoxic. Compound 1 may have potential as an anti-angiogenic and anti-tumor agent.
Hussain
S
S
School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester, UK.
Gaffney
J
J
Ahmed
N
N
Slevin
M
M
Iqbal Choudhary
M
M
Ahmad
V U
VU
Qasmi
Z
Z
Abbasi
M A
MA
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001562:Benzimidazoles; D003517:Cyclopentanes; D004354:Drug Screening Assays, Antitumor; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D024301:Plant Bark / Q000737:chemistry; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*
C436284:2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D003517:Cyclopentanes; D006027:Glycosides; C539873:symplocomoside; C539874:symponoside; D013939:Thymidine Phosphorylase