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Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.

Published version
Peer-reviewed

Type

Article

Change log

Authors

de Montes, Enrique Gil 
Guerreiro, Ana 

Abstract

Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C-C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody-drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.

Description

Keywords

Animals, Antineoplastic Agents, Biological Products, Humans, Mice, Oxidation-Reduction, Prodrugs, Quinones

Journal Title

Nat Chem

Conference Name

Journal ISSN

1755-4330
1755-4349

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
European Commission Horizon 2020 (H2020) Marie Sklodowska-Curie actions (792495)
Biotechnology and Biological Sciences Research Council (1795534)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
Cancer Research UK (A25117)
European Research Council (812994)
European Commission (EC) (852985)
Medical Research Council (MC_PC_17230)
European Research Council (676832)