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Toward aplyronine payloads for antibody–drug conjugates: total synthesis of aplyronines A and D

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Abstract

The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody–drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.

Graphical abstract: Toward aplyronine payloads for antibody–drug conjugates: total synthesis of aplyronines A and D

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Publication details

The article was received on 30 Dec 2017, accepted on 29 Jan 2018 and first published on 02 Feb 2018


Article type: Paper
DOI: 10.1039/C7OB03204H
Citation: Org. Biomol. Chem., 2018, Advance Article
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    Toward aplyronine payloads for antibody–drug conjugates: total synthesis of aplyronines A and D

    N. Anžiček, S. Williams, M. P. Housden and I. Paterson, Org. Biomol. Chem., 2018, Advance Article , DOI: 10.1039/C7OB03204H

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