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

• Published in: Bioorganic chemistry Vol. 115; p. 105256
• Main Authors: Li, Yanchun, Ai, Xinyu, Zou, Chunyang, Liu, Yutong, Ma, Lili, Men, Jinyu, Liu, Dongyue, Sheng, Lei, Ruan, Xinhui, Liu, Haihan, Li, Weixia, Ma, Enlong, Yuan, Lei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2021
• Subjects: Anti-metastatic ability in vitro and in vivo; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Asperphenamate; Cathepsin inhibitors; Cathepsin L - antagonists & inhibitors; Cathepsin L - metabolism; Cell Line; Cell Proliferation - drug effects; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Design and synthesis; Docking study; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Structure-Activity Relationship; Asperphenamate; Docking study; Cathepsin inhibitors; Anti-metastatic ability in vitro and in vivo; Design and synthesis
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105256

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•Forty-four B-ring derivatives of asperphenamate were designed and synthesized.•Compound B-2a displayed a good selectivity against cathepsin L.•Toxicity evaluation indicated that B-2a displayed no toxicity toward normal cells.•Wound-healing assay showed B-2a had an anti-metastatic effect in vitro.•The in vivo anti-metastatic ability was validated by mouse models.
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.