Harnessing the Reactivity of Duclauxin toward Obtaining h PTP1B 1-400 Inhibitors.

Duclauxin ( 1 ) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) ( h PTP1B 1-400 ), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a , 6 , and 7 . Moreover, a one-/two-step semisynthetic approach guided by docking toward h PTP1B 1-400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 ( 8a - 15a , 36a , and 37a ) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 ( 5b , 11b - 37b ). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin ( 1 ) and 36b were assessed for their potential acute toxicity, estimating their LD 50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.