Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

Virginia A. McNally; Mehdi Rajabi; Abdul Gbaj; Ian J. Stratford; Philip N. Edwards; Kenneth T. Douglas; Richard A. Bryce; Mohammed Jaffar; Sally Freeman

doi:10.1211/jpp.59.4.0008

Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

Virginia A. McNally, Mehdi Rajabi, Abdul Gbaj, Ian J. Stratford, Philip N. Edwards, Kenneth T. Douglas, Richard A. Bryce, Mohammed Jaffar, Sally Freeman

Research output: Contribution to journal › Article › peer-review

Abstract

A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding. © 2007 The Authors.

Original language	English
Pages (from-to)	537-547
Number of pages	10
Journal	Journal of Pharmacy and Pharmacology
Volume	59
Issue number	4
DOIs	https://doi.org/10.1211/jpp.59.4.0008
Publication status	Published - Apr 2007

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title = "Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase",

abstract = "A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding. {\textcopyright} 2007 The Authors.",

author = "McNally, {Virginia A.} and Mehdi Rajabi and Abdul Gbaj and Stratford, {Ian J.} and Edwards, {Philip N.} and Douglas, {Kenneth T.} and Bryce, {Richard A.} and Mohammed Jaffar and Sally Freeman",

year = "2007",

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doi = "10.1211/jpp.59.4.0008",

language = "English",

volume = "59",

pages = "537--547",

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T1 - Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

AU - McNally, Virginia A.

AU - Rajabi, Mehdi

AU - Gbaj, Abdul

AU - Stratford, Ian J.

AU - Edwards, Philip N.

AU - Douglas, Kenneth T.

AU - Bryce, Richard A.

AU - Jaffar, Mohammed

AU - Freeman, Sally

PY - 2007/4

Y1 - 2007/4

N2 - A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding. © 2007 The Authors.

AB - A series of novel imidazolyluracil conjugates were rationally designed and synthesised to probe the active site constraints of the angiogenic enzyme, thymidine phosphorylase (TP, E.C. 2.4.2.4). The lead compound in the series, 15d, showed good binding in the active site of human TP with an inhibition in the low μM range. The absence of a methylene bridge between the uracil and the imidazolyl subunits (series 16) decreased potency (up to 3-fold). Modelling suggested that active site residues Arg202, Ser217 and His116 are important for inhibitor binding. © 2007 The Authors.

U2 - 10.1211/jpp.59.4.0008

DO - 10.1211/jpp.59.4.0008

M3 - Article

SN - 2042-7158

VL - 59

SP - 537

EP - 547

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

IS - 4

ER -

Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

Abstract

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