[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
148 Rational design and synthesis of novel thymidine phosphorylase inhibitors as anti-angiogenic agents. Virginia A McNally, Paul E Murray, Chris Cole, Stacey D Lockyer, Ian J Stratford, Mohammed Jaffar & Sally Freeman. School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
The angiogenic growth factor thymidine phosphorylase (TP, PD-ECGF, EC 2.4.2.4) has been identified as an important target in the advancement of cancer therapy (Bicknell et al, 1994; Cole et al, 1999). TP is upregulated in several tumour types, (Reynolds et al 1994; Moghaddam et al 1995) and TP expression has been correlated to increased microvessel density (angiogenesis) in breast, colon and gastric cancers (Toi et al 1995; Maeda et al 1996). In addition, TP confers resistance to apoptosis (Griffiths et al 1997) and promotes metastasis, therefore TP inhibition maybe used in cancer chemotherapy.
TP catalyses the reversible phosphorlysis of thymidine to thymine and 2-deoxyribose-1-phosphate. It has been suggested that TP's angiogenic activity is the result of its enzymatic by-products (Haraguchi et al 1994).
Based on molecular modelling studies, we have identified the important binding residues within the active site for the design of novel TP inhibitors. We have rationally synthesised a range of novel N(1)- and 6-substituted uracils (where X = H, Me, Cl, Br and R = imidazolyl, furyl, pyridyl) to maximise the interaction between the drug and the active site.
Some of the compounds synthesised showed greater potency than the known inhbitor 6-amino-5-bromouracil [1] (IC50 1.05 mM). The introduction of a halo group (Br, Cl) at C-5 increases inhibiton. In general, substitution at C-6 improved potency by a factor of 5 when compared to the N(1)-substituted compounds (IC50s between 0.5-0.2 mM).
The work was funded by Oxford Biomedica, BBSRC, AICR and MRC. |
