A dimeric urea of the bisabolene sesquiterpene from the Okinawan marine sponge Axinyssa sp. inhibits protein tyrosine phosphatase 1B activity in Huh-7 human hepatoma cells.

Abstract Protein tyrosine phosphatase 1B (PTP1B) plays an important role as a negative regulator of the insulin and leptin signaling pathways. Therefore, this enzyme is regarded as an attractive therapeutic target for the treatment of type 2 diabetes and obesity. Our screening program for PTP1B inhibitors led to the isolation of four sesquiterpenes and sterol: N , N ′-bis[(6 R ,7 S )-7-amino-7,8-dihydro-α-bisabolen-7-yl]urea ( 1 ), (6 R ,7 S )-7-amino-7,8-dihydro-α-bisabolene ( 2 ), (1 R ,6 S ,7 S ,10 S )-10-isothiocyanato-4-amorphene ( 3 ), axinisothiocyanate J ( 4 ), and axinysterol ( 5 ) from the marine sponge Axinyssa sp. collected at Iriomote Island. Of these, compound 1 was the most potent inhibitor of PTP1B activity (IC 50  = 1.9 μM) without cytotoxicity at 50 μM in two human cancer cell lines, hepatoma Huh-7 and bladder carcinoma EJ-1 cells. Compound 1 also moderately enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells. Therefore, compound 1 has potential as a new type of anti-diabetic drug candidate possessing PTP1B inhibitory activity.