Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells.

Yanchun Li, Xinyu Ai, Chunyang Zou, Yutong Liu, Lili Ma, Jinyu Men, Dongyue Liu, Lei Sheng, Xinhui Ruan, Haihan Liu, Weixia Li, Enlong Ma, Lei Yuan

Bioorganic chemistry 2021 Oct

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Asperphenamate is a natural product that has attracted considerable interest from researchers worldwide. In the last decade, aiming to increase the biological activity and improve druggability, modifications of the A-ring moiety in asperphenamate have been performed. Our laboratory has also recently reported functional derivatizations of the A ring and studied its effect on the inhibition of cysteine cathepsin L. However, the functional significance of the B-ring fragment toward cathepsin L has not been evaluated thus far. In this paper, forty-four derivatives of the B-ring substituted with different N-phenylsulfonyl groups were designed and synthesized. Among them, the paratrifluromethyl analog B-2a and the 2, 4-difluoro-5-chloro derivative B-11b showed more potent inhibitory activity against cathepsin L than the control compound, ABR, which displayed the strongest inhibitory effect on cathepsin L and S among all reported asperphenamate derivatives. In particular, compound B-2a showed more pronounced selectivity against cathepsin L than the other derivatives. Molecular docking revealed that the N-phenylsulfonylamide moiety was vital for the interactions between B-2a and cathepsin L. Moreover, B-2a displayed no toxicity against normal cells. Therefore, compound B-2a was selected for further studies. Wound-healing assays, Transwell chamber assays and breast cancer lung metastasis mouse models demonstrated that B-2a exhibited antimetastatic ability in vitro and in vivo. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Yanchun Li, Xinyu Ai, Chunyang Zou, Yutong Liu, Lili Ma, Jinyu Men, Dongyue Liu, Lei Sheng, Xinhui Ruan, Haihan Liu, Weixia Li, Enlong Ma, Lei Yuan. Discovery of a novel and selective cathepsin L inhibitor with anti-metastatic ability in vitro and in vivo against breast cancer cells. Bioorganic chemistry. 2021 Oct;115:105256