Synthesis and Evaluation of Dolastatin 10 Analogues Containing Heteroatoms on the Amino Acid Side Chains

Synthetic analogues of the natural occurring dolastatin 10 are of great interest in cancer due to their potent in vitro activity and their uses as payloads in antibody drug conjugates (ADCs). Modification of the dolastatin 10 core scaffold has mainly focused on modifications of the P1, N-terminus, a...

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Published inJournal of natural products (Washington, D.C.) Vol. 80; no. 9; pp. 2484 - 2491
Main Authors Dugal-Tessier, Julien, Barnscher, Stuart D, Kanai, Akira, Mendelsohn, Brian A
Format Journal Article
LanguageEnglish
Published United States American Chemical Society and American Society of Pharmacognosy 22.09.2017
Subjects
Amino Acids - chemistry
Amino Acids - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Azides - chemistry
Azides - pharmacology
Depsipeptides - chemical synthesis
Depsipeptides - chemistry
Depsipeptides - pharmacology
Humans
Molecular Structure
Oligopeptides - chemistry
Oligopeptides - pharmacology
Phenylalanine - chemistry
Phenylalanine - pharmacology
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Summary:Synthetic analogues of the natural occurring dolastatin 10 are of great interest in cancer due to their potent in vitro activity and their uses as payloads in antibody drug conjugates (ADCs). Modification of the dolastatin 10 core scaffold has mainly focused on modifications of the P1, N-terminus, and P5, C-terminus, with minimal attention to the P2 subunit. In this paper we discuss the introduction of heteroatoms to the P2 side chain, which results in potent activity in vitro. The most active compounds contained azides in the P2 unit and required a phenylalanine-derived P5 subunit.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.7b00359