Cathepsin D inhibitors based on tasiamide B derivatives with cell membrane permeability. (1st March 2022)

• Record Type: Journal Article
• Authors: Li, Zhi; Li, Hang; Jiang, Fan; Wang, Zhaolin; Zhang, Wei
• Is Part Of: Bioorganic & medicinal chemistry. Volume 57(2022)
• Publication Date: 2022-03-01
• Subjects: Cathepsin D inhibitors -- Bioconjugate -- Tasiamide B derivatives -- Cell penetrating peptide -- Anti-cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116646
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Cathepsin D (Cath D) has been evidenced as a potential target for cancer therapy. Our previous studies revealed that TB-9, a tasiamide B derivative, exhibited highly potent inhibition against Cath D with satisfactory selectivity over Cath E and BACE1. But this compound was inactive on cell level possibly due to poor membrane permeability. Herein, we report the design, synthesis, and evaluation of two novel Cath D inhibitors (2 and 3 ) which combining tasiamide B scaffold with a cell penetrating peptide (CPP) specifically targeting the endolysosomal compartment. The results revealed that 2 and 3 not only retained highly potent inhibition against Cath D, but also were active against MDA-MB-231 cell lines.