7‐Deazaxanthine, a novel prototype inhibitor of thymidine phosphorylase

Abstract

7-Deazaxanthine (7DX) was identified as a novel inhibitor of thymidine (dThd) phosphorylase (TPase). It inhibited the TPase reaction in a concentration-dependent manner. At 1 mM, it almost completely prevented the TPase-catalysed hydrolysis of dThd to thymine. The 50% inhibitory concentration (IC SH ) of 7DX was 40 W WM in the presence of 100 W WM of the natural substrate dThd. 7DX is also endowed with a marked inhibitory effect on angiogenesis. It significantly prevents neovascularisation in the chicken chorioallantoic membrane during development. 7DX is the first purine derivative shown to be a potent inhibitor of purified TPase and angiogenesis.z 1998 Federation of European Biochemical Societies.

5′-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis

“…Original magnification, 15ϫ. (Balzarini et al, 1998;Liekens et al, 2002). In addition, KIN59, which represents the first compound that inhibits TPase activity without interacting with the substrate-binding sites of the enzyme, displayed a potent antiangiogenic activity in the CAM assay (Liekens et al, 2004).…”

“…Since 1998, our research groups have been involved in the search for novel TPase inhibitors. We have described 7-deazaxanthine as the first purine derivative able to inhibit TPase (Balzarini et al, 1998), and TP65 as the first multisubstrate inhibitor of TPase Esteban-Gamboa et al, 2000;Pérez-Pérez et al, 2005). These compounds also inhibited angiogenesis in the chick chorioallantoic membrane (CAM) assay (Balzarini et al, 1998;Liekens et al, 2002).…”

The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action

“…Based on the structure of E. coli TPase, we designed and synthesized the first purine derivative (7DX) with inhibitory activity against E. coli TPase (16). 7DX was used as a lead compound to develop a novel type of multisubstrate analogue inhibitors of TPase.…”

“…Based on the structure of Escherichia coli TPase (14), which shows 40% sequence identity with human TPase (15), we recently designed and synthesized the first purine derivative (7-deazaxanthine (7DX)) with inhibitory activity against E. coli TPase (16). 7DX was then used as a lead compound to develop more potent purine-based multisubstrate inhibitors of TPase (17).…”

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule “crystallization chaperone” 5′-O-tritylinosine (KIN59)

“…In fact, a combination of TPI and TFT (designated TAS-102) is currently being evaluated in clinical trials for the treatment of various solid tumors, including metastatic colon and breast carcinomas [15,16]. Our research groups have described 7-deazaxanthine (7-DX), the first purine derivative with inhibitory activity against TP and angiogenesis in the 'chicken chorioallantoic membrane' (CAM) assay [17], and also TP65 (9-[8-phosphonooctyl]-7-deazaxanthine), the first multisubstrate inhibitor of TP that was shown to interact with both the thymidine and the phosphate binding site of TP [18,19]. More recently, we identified the purine nucleoside 5 0 -O-tritylinosine as a novel TP inhibitor [20,21], in which the presence of the trityl moiety was proven to be crucial for both its inhibitory activity against TP and its anti-angiogenic effect in the CAM assay.…”