Critical role of the linking amide in CC-1065 and the duocarmycins:Implications on the source of DNA alkylation catalysis

Tools

Boger, Dale L., Santillán, Alejandro, Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 and Jin, Qing (1998) Critical role of the linking amide in CC-1065 and the duocarmycins:Implications on the source of DNA alkylation catalysis. Journal of the American Chemical Society, 120 (45). pp. 11554-11557. ISSN 0002-7863

Full text not available from this repository.

Abstract

The preparation and evaluation of both enantiomers of 5 are described and it constitutes an analogue of CBI-TMI (4), the duocarmycins, and CC-1065 in which the amide linking the alkylation and DNA binding subunits has been replaced by a methylene. The agent proved remarkably stable to acid-catalyzed solvolysis consistent with alkylation subunit stabilization derived from a fully engaged vinylogous amide. It was found to exhibit an acid-catalyzed solvolysis half-life (t( 1/2 )) of 80 h, 824 h, and ca. 30 500 h (3.3 days, 34 days, and ca. 3.5 years) at pH 1, 2, and 3, respectively, and to be completely stable at pH 7. The removal of the linking amide resulted in a 105-fold loss in cytotoxic potency and the complete loss of DNA alkylation capabilities providing an agent that is > 106x less effective than 4 and > 102x less effective than even N-BOC-CBI or N-Ac-CBI. These observations highlight the critical importance of the linking amide and implicate a fundamental role in DNA alkylation catalysis. Thus, rather than enhancing DNA alkylation by facilitating C4 carbonyl protonation (acid catalysis), the removal of the linking amide abolished the capabilities for DNA alkylation. This is consistent with the intimate participation of the linking amide in catalysis derived from a DNA binding-induced conformation change that serves to disrupt the alkylation subunit cross-conjugated vinylogous amide stabilization activating the agents for nucleophilic attack.

Item Type: Article
Uncontrolled Keywords: catalysis,chemistry(all),biochemistry,colloid and surface chemistry ,/dk/atira/pure/subjectarea/asjc/1500/1503
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 03 Oct 2022 12:31
Last Modified: 24 Oct 2022 15:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/88816
DOI: 10.1021/ja9818093

Actions (login required)

View Item View Item