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Mechanism of Action of AminoCBIs: Highly Reactive but Highly Cytotoxic Analogues of the Duocarmycins
Author(s) -
Tercel Moana,
Pruijn Frederik B.,
O'Connor Patrick D.,
Liyanage H. D. Sarath,
Atwell Graham J.,
Alix Sonia M.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402256
Subject(s) - solvolysis , chemistry , protonation , cytotoxicity , reactivity (psychology) , stereochemistry , hydrolysis , reactive intermediate , cytotoxic t cell , mechanism of action , combinatorial chemistry , biochemistry , organic chemistry , in vitro , medicine , ion , alternative medicine , pathology , catalysis
Duocarmycins are highly cytotoxic natural products that have potential for development into anticancer agents. Herein we describe proposed but previously unidentified NH analogues of the DNA‐alkylating subunit and characterise these by solvolysis studies, NMR and computational modelling. These compounds are shown to be the exclusive intermediates in the solvolysis of their seco precursors and to possess very similar structural features to the widely studied O‐based analogues, apart from an unusually high basicity. The measured p K a of 10.5 implies that the NH compounds are fully protonated under physiological conditions. Remarkably, their extremely high reactivity (calculated hydrolysis rate 10 8 times higher for protonated NH compared to the neutral O analogue) is still compatible with potent cytotoxicity, provided the active species is formed in the presence of cells. These surprising findings are of relevance to the design of duocarmycin‐based tumour‐selective therapies.