Anti‐angiogenic activity of a novel multi‐substrate analogue inhibitor of thymidine phosphorylase

FEBS Letters

Bilsen, Filip²  De Clercq, Erik²  Liekens, Sandra²  Pérez-Pérez, Marı́a-Jesús¹  Balzarini, Jan²  Camarasa, Marı́a-José¹  Priego, Eva Marı́a¹ 

[1] Instituto de Quı́mica Médica, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain;Rega Institute for Medical Research, Minderbroedersstraat 10, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

关键词: 7-Deazaxanthine;    Thymidine phosphorylase;    Angiogenesis;    Multi-substrate analogue inhibitor;    9-(8-Phosphonooctyl)-7-deazaxanthine;    Endothelial cell;   

DOI  :  10.1016/S0014-5793(01)03233-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

7-Deazaxanthine (7-DX) was recently identified as the first purine derivative with pronounced inhibitory activity against Escherichia coli thymidine phosphorylase (TP) and angiogenesis. In order to ‘freeze’ the enzyme in an open, inactive conformation, a novel multi-substrate analogue inhibitor of TP, containing an alkyl phosphonate moiety covalently linked to 7-DX, was synthesized. The prototype compound TP65 (9-(8-phosphonooctyl)-7-deazaxanthine) (at 250 μM) completely inhibited TP-induced formation of microvascular sprouts from endothelial cell aggregates in a three-dimensional fibrin gel. In the chick chorioallantoic membrane assay, TP caused a dose-dependent stimulation of angiogenesis, which was completely inhibited by 250 nmol TP65. This dose proved to be non-toxic for the developing chick embryo. TP65 thus emerges as a potent and specific inhibitor of TP and TP-induced angiogenesis, which opens new perspectives for multi-substrate analogue inhibitors of TP as potential anti-cancer agents and as inhibitors of angiogenesis and of diseases with enhanced expression of TP.

【 授权许可】

Unknown