Design and synthesis of dual cathepsin L and S inhibitors and antimetastatic activity evaluation in pancreatic cancer cells.

Abstract

Currently, the migration and invasion of cancer cells remain the main factors of poor prognosis in the majority of cancer patients. Developing an effective antimetastatic agent is crucial for cancer therapy. Our recent research revealed that Cat L and S are expressed concurrently in metastatic pancreatic cancer cells. Asperphenamate analog ASPER-29, which exhibits dual Cat L and S inhibitory potency, showed a definite antimetastatic effect on pancreatic cancer BxPC-3 and PANC-1 cells. To further improve the antimetastatic ability of asperphenamate-type molecules, 24 derivatives were designed and synthesized by a scaffold-hopping strategy. The cathepsin inhibitory activity assay results showed that most of the derivatives exhibited dual inhibitory effects on Cat L and S. Among all derivatives, Compound B1a showed the strongest inhibitory activity, with IC50 values of 4.10 ± 0.14 μM and 1.79 ± 0.11 μM, which were 1.5-fold and 2.8-fold more potent than those of positive drugs against Cat L and S, respectively. Further wound-healing and transwell chamber assays demonstrated that B1a presented significant antimetastatic ability in vitro.

• Authors: Haoqiang Huang, Yi Zhang, Xiaohong Xu, Yongzheng Liu, Juanping Zhao, Lili Ma, Jie Lei, Wentao Ge, Ning Li, Enlong Ma, Yanchun Li, Lei Yuan
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 80 Pg. 129087 (01 15 2023) ISSN: 1464-3405 [Electronic] England
• PMID: 36427655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cathepsin L
• Cathepsins
• ASPER-29

Topics

• Humans
• Antineoplastic Agents (pharmacology)
• Cathepsin L (metabolism)
• Cathepsins
• Cell Line, Tumor
• Cell Proliferation
• Pancreatic Neoplasms (drug therapy)
• Structure-Activity Relationship