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CC BY 4.0 · Pharmaceutical Fronts
DOI: 10.1055/s-0044-1787282
Original Article

Modification and Structure–Activity Relationship Study of Cyclodepsipeptide Trichodestruxin D Derivatives as Potential Antitumor Agents

Jihua Zou‡   #
1   College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China
,
Yifei Lu‡   #
1   College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China
,
Xiang Li
2   Department of Organic Chemistry, College of Pharmacy, Naval Medical University, Shanghai, People's Republic of China
,
Conghao Gai
2   Department of Organic Chemistry, College of Pharmacy, Naval Medical University, Shanghai, People's Republic of China
,
Yan Zou
2   Department of Organic Chemistry, College of Pharmacy, Naval Medical University, Shanghai, People's Republic of China
,
Qingjie Zhao
1   College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China
2   Department of Organic Chemistry, College of Pharmacy, Naval Medical University, Shanghai, People's Republic of China
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Abstract

Trichodestruxins A–D are cyclic peptides isolated from the plant endophyte fungus Trichoderma harzianum with inhibitory activities against the proliferation of tumor cells. This study aimed to modify the structure of trichodestruxin D (TD-(R)) to improve its antitumor activity and analyze the structure–activity relationship (SAR) to provide references for lead optimization. In this study, seven TD-(R) derivatives (TD-(S), TD-1, 2, 3, 4, 5, 6) were designed by different strategies, namely amino acid mutation, configuration switching, replacement of ester with amide, and N-methylation/demethylation. Those derivatives were prepared by a solid-phase peptide synthesis strategy, and structurally characterized by high-resolution mass spectra. The inhibitory activities of the peptides against the lung carcinoma A549 cells were assessed by determining cellular proliferation and migration using CCK-8 and a 24-well migration plate. Our data confirmed the inhibitory effect of those derivatives on A549 cell proliferation, among which TD-(S), TD-1, and TD-2 displayed higher inhibitory activity compared with the control (DMSO) group, but their inhibitory activity was slightly decreased than that of TD-(R). The inhibitory activity of TD-3, TD-4, and TD-6 on A549 cell migration was much better than that of TD-(R). SAR studies demonstrated a pivotal role in the configuration of the residue of 2-hydroxy-4-methyl-pentenoic acid and some residues in the structure of TD-(R). In conclusion, TD-3, TD-4, and TD-6 may be potential agents for the treatment of cancer migration, and our modification methods will provide a reference for the development of anticancer drugs in the future.

Keywords

cyclodepsipeptides - cyclic peptide - cell migration

# These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 15 November 2023

Accepted: 08 May 2024

Article published online:
31 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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