A unique class of duocarmycin and CC-1065 analogues subject to reductive activation.

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Research Abstract Details 

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A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Abstract Text:

Wei Jin,John D Trzupek,Thomas J Rayl,Melinda A Broward,George A Vielhauer,Scott J Weir,Inkyu Hwang,Dale L Boger,Wei Jin,John D Trzupek,Thomas J Rayl,Melinda A Broward,George A Vielhauer,Scott J Weir,Inkyu Hwang,Dale L Boger,

N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Publishing Authors By Initials

W Jin,JD Trzupek,TJ Rayl,MA Broward,GA Vielhauer,SJ Weir,I Hwang,DL Boger,W Jin,JD Trzupek,TJ Rayl,MA Broward,GA Vielhauer,SJ Weir,I Hwang,DL Boger,

For similar pharmaceutical preparations: prodrugs research abstracts see: pharmaceutical preparations: prodrugs research

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A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 15391-7

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 1520-5126

DAY: 17

MONTH: 11

YEAR: 2007

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Keywords Mesh Terms:

KEYWORDS: Prodrugs

MESH TERMS: pharmacology

Chemical & Substance for Abstract: A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. Information

Substance Name: DNA

Registry Number: 9007-49-2

Grant and Affiliation Information for A unique class of duocarmycin and CC-1065 analogues subject to reductive activation.

AFFILIATION: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA41986

ACRONYM: CA

MEDLINETA: J Am Chem Soc

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