Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Peter Thomson; Matthew A. Naylor; Steven A. Everett; Michael R. L. Stratford; Gemma Lewis; Sally Hill; Kantilal B. Patel; Peter Wardman; Peter D. Davis

doi:10.1158/1535-7163.MCT-06-0429

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Peter Thomson, Matthew A. Naylor, Steven A. Everett, Michael R. L. Stratford, Gemma Lewis, Sally Hill, Kantilal B. Patel, Peter Wardman, Peter D. Davis

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

38 Citations (Scopus)

Abstract

NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.

Original language	English
Pages (from-to)	2886-2894
Number of pages	9
Journal	Molecular Cancer Therapeutics
Volume	5
Issue number	11
DOIs	https://doi.org/10.1158/1535-7163.MCT-06-0429
Publication status	Published - Nov 2006

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@article{976481ec84ad410da9e8d81b47bf7566,

title = "Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4",

abstract = "NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.",

author = "Peter Thomson and Naylor, {Matthew A.} and Everett, {Steven A.} and Stratford, {Michael R. L.} and Gemma Lewis and Sally Hill and Patel, {Kantilal B.} and Peter Wardman and Davis, {Peter D.}",

note = "dc.publisher: American Association for Cancer Research ",

year = "2006",

month = nov,

doi = "10.1158/1535-7163.MCT-06-0429",

language = "English",

volume = "5",

pages = "2886--2894",

journal = "Molecular Cancer Therapeutics",

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T1 - Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

AU - Thomson, Peter

AU - Naylor, Matthew A.

AU - Everett, Steven A.

AU - Stratford, Michael R. L.

AU - Lewis, Gemma

AU - Hill, Sally

AU - Patel, Kantilal B.

AU - Wardman, Peter

AU - Davis, Peter D.

N1 - dc.publisher: American Association for Cancer Research

PY - 2006/11

Y1 - 2006/11

N2 - NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.

AB - NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.

U2 - 10.1158/1535-7163.MCT-06-0429

DO - 10.1158/1535-7163.MCT-06-0429

M3 - Article

C2 - 17121936

SN - 1535-7163

VL - 5

SP - 2886

EP - 2894

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 11

ER -

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

Abstract

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