title: Mechanism of action of AminoCBIs: highly reactive but highly cytotoxic analogues of the duocarmycins.
abstract: 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 pKa 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.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand). m.tercel@auckland.ac.nz.
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
authors.forename: Patrick D
authors.initials: PD
authors.lastname: O'Connor
authors.forename: H D Sarath
authors.initials: HD
authors.lastname: Liyanage
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Alix
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity*; D007700:Kinetics; D051379:Mice; D011522:Protons; D011758:Pyrroles / Q000494:pharmacology
chemical_list: C506823:1,2,9,9a-tetrahydrocyclopropa(1,2-c)benz(1,2-e)indol-4-one; D000903:Antibiotics, Antineoplastic; D003521:Cyclopropanes; D000080890:Duocarmycins; D007211:Indoles; D011522:Protons; D011758:Pyrroles; C066098:duocarmycin SA
keywords: antitumor agents; basicity; biological activity; computational chemistry; duocarmycins