Design, synthesis, and bioactivities of tasiamide B derivatives as cathepsin D inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Cathepsin D (Cath D) is overexpressed in tumors and promotes cancer progression.
• Cath D is a validated therapeutic target for cancer treatment.
• Previous tasiamide B derivatives showed potent inhibition but had high molecular weights.

Purpose of the Study:

• To design and synthesize novel tasiamide B derivatives with lower molecular weights.
• To evaluate the inhibitory activity and selectivity of new derivatives against Cath D, Cath E, and BACE1.
• To identify a lead compound for developing potent and selective Cath D inhibitors.

Main Methods:

• Design and synthesis of two series of tasiamide B derivatives.
• Enzymatic assays to determine inhibitory activity (IC50) against Cath D, Cath E, and BACE1.
• Evaluation of selectivity profiles for the synthesized compounds.

Main Results:

• Compound 1, a novel derivative, demonstrated potent inhibition of Cath D with an IC50 of 3.29 nM.
• Compound 1 exhibited significant selectivity over Cath E (72-fold) and BACE1 (295-fold).
• The new derivatives possess lower molecular weights compared to previous compounds.

Conclusions:

• Compound 1 is a highly potent and selective inhibitor of Cathepsin D.
• This compound serves as a valuable template for the development of novel cancer therapeutics targeting Cath D.
• The optimized derivatives offer potential for improved drug design in cancer treatment.