Shishicrellastatins, inhibitors of cathepsin B, from the marine sponge Crella (Yvesia) spinulata

Design, Synthesis, and Structure–Activity Relationship Study of Epoxysuccinyl–Peptide Derivatives as Cathepsin B Inhibitors

“…After removing the solvent under vacuum, the mixture was poured into 400 mL of deionized water and extracted with 400 mL of AcOEt by a separatory funnel. The combined organic layers were washed with 200 mL of NaHCO 3 -brine and dried over MgSO 4 In a round-bottom flask containing 7 (tert-butoxycarbonyl (Boc)-L-methionine; 0.031 mol; 7.7 g), 8a (hexylamine from Alfa Aesar; 0.031 mol; 3.13 g), and 1-hydroxybenzotriazole (0.031 mol; 4.19 g) in AcOEt, a solution of N,N′-dicyclohexylcarbodiimide (0.031 mol; 6.39 g) dissolved in AcOEt was added dropwise, and the mixture was stirred at 5°C for 1.5 h. The solution was then warmed to room temperature and stirred for 2.5 h. The reaction mixture was filtered and washed with AcOEt. The organic layer was washed with 5% HCl and saturated NaHCO 3 -brine solution, dried over MgSO 4 , and filtered.…”

“…The aqueous phase was alkalified with 25% NaOH (pH >10) and washed with AcOEt. The combined AcOEt layers were washed with brine and dried over MgSO 4 . Removal of AcOEt yielded 2.55 g of 10a (0.011 mol; 90%) as a yellow oil, which was used directly in the next step.…”

“…3,4) Therefore, cathepsin B has been selected as a potential target for the treatment of a variety of human cancers, including kidney cancer, lung cancer, and liver cancer. 5,6) In order to achieve effective cancer treatment, it is of great importance to locate the active site of cathepsin B and to develop specific inhibitors.…”

“…7) In the past few years, extensive work has been conducted to develop effective cathepsin B inhibitors for potential cancer treatment. 4) For example, Katunuma has reported the synthesis of a derivative of the epoxysuccinyl-peptide cathepsin B inhibitor by covalently linking its ethylene oxide with the thiol group of the Cys29 residue of cathepsin B. 8) In addition, Sadaghiani et al have synthesized two interesting compounds: E64d and CA-074 (1 and 2 as shown in Fig.…”

Crellasterones A and B: A-Norsterol Derivatives from the New Caledonian Sponge Crella incrustans

“…Sponges from the genus Crella have not been widely studied, with only a few natural products isolated, including crellastatins A–M, [8,9,10] shishicrellastatins A and B [11], norselic acids A–E [12] and benzylthiocrellidone [13]. Crellastatin A, a dimeric 4,4′-dimethylsterol from Crella sp.…”