Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase

Christian Cole; Philip Reigan; Abdul Gbaj; Philip N. Edwards; Kenneth T. Douglas; Ian J. Stratford; Sally Freeman; Mohammed Jaffar

doi:10.1021/jm020964w

Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase

Christian Cole, Philip Reigan, Abdul Gbaj, Philip N. Edwards, Kenneth T. Douglas, Ian J. Stratford, Sally Freeman, Mohammed Jaffar

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

Abstract

Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2′-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-amino-imidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2′-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 μM. This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.

Original language	English
Pages (from-to)	207-209
Number of pages	2
Journal	Journal of Medicinal Chemistry
Volume	46
Issue number	2
DOIs	https://doi.org/10.1021/jm020964w
Publication status	Published - 16 Jan 2003

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title = "Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase",

abstract = "Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2′-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-amino-imidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2′-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 μM. This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.",

author = "Christian Cole and Philip Reigan and Abdul Gbaj and Edwards, {Philip N.} and Douglas, {Kenneth T.} and Stratford, {Ian J.} and Sally Freeman and Mohammed Jaffar",

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T1 - Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase

AU - Cole, Christian

AU - Reigan, Philip

AU - Gbaj, Abdul

AU - Edwards, Philip N.

AU - Douglas, Kenneth T.

AU - Stratford, Ian J.

AU - Freeman, Sally

AU - Jaffar, Mohammed

PY - 2003/1/16

Y1 - 2003/1/16

N2 - Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2′-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-amino-imidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2′-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 μM. This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.

AB - Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2′-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-amino-imidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 ∼ 20 nM). Contrastingly, the corresponding 2′-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 μM. This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.

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DO - 10.1021/jm020964w

M3 - Article

SN - 0022-2623

VL - 46

SP - 207

EP - 209

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase

Abstract

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