Penostatin Derivatives, a Novel Kind of Protein Phosphatase 1B Inhibitors Isolated from Solid Cultures of the Entomogenous Fungus Isaria tenuipes

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Therefore, small molecular inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes diseases. In a continuing search for new protein phosphatase inhibitors from fungi, we have isolated a new compound, named penostatin J (1), together with three known ones, penostatin C (2), penostatin A (3), and penostatin B (4), from cultures of the entomogenous fungus Isaria tenuipes. The structure of penostatin J (1) was elucidated by extensive spectroscopic analysis. We also demonstrate for the first time that penostatin derivatives exhibit the best PTP1B inhibitory action. These findings suggest that penostatin derivatives are a potential novel kind of PTP1B inhibitors.

Bioactive Compounds Produced by Strains of Penicillium and Talaromyces of Marine Origin

“…Therefore, this compound was introduced as a prospect therapeutic drug for the treatment of type II diabetes [ 140 ]. Inhibitory properties towards PTP1B were also disclosed for penostatins A–C [ 211 ], while verruculides A and B respectively displayed a strong and a moderate effect against this enzyme [ 173 ]. Finally, a moderate effect as an inhibitor of tyrosine kinases was reported for terrestrol G ( Figure 2 ) [ 64 ].…”

PTP1B Inhibitors from the Entomogenous Fungi Isaria fumosorosea

“…PTP1B activity was measured as the rate of hydrolysis of p -nitrophenyl phosphate (pNPP) in a 96-well microtiter plate format [ 13 ]. Sodium orthovanadate was used as the positive control.…”

Marine-Derived Penicillium Species as Producers of Cytotoxic Metabolites

“…Moreover, penostatin C ( 169 ) exhibited significant cytotoxicity in seven of the 36 cell lines tested with ED 50 values ranging from 1 to 2 μg/mL. Recent studies have shown that penostatins A–C ( 167 – 169 ) may be tyrosine phosphatase 1B (PTP1B) inhibitors, which can be used to treat type II diabetes and other associated metabolic diseases (IC 50 = 15.87, 33.65, and 0.37 μM, respectively), while sodium orthovanadate was used as a positive control with an IC 50 value of 0.65 μM [ 113 ]. The total synthesis of penostatins A, B, and F ( 167 , 168 , 172 ) was previously reported [ 114 , 115 ].…”

“…OUPS-79 Marine alga Polyketide P388 0.8 μg/mL PTP1B inhibitor (IC 50 = 15.87 μM) [ 111 , 113 ] Penostatin B ( 168 ) Penicillium sp. OUPS-79 Marine alga Polyketide P388 1.2 μg/mL PTP1B inhibitor (IC 50 = 33.65 μM) [ 111 , 113 ] Penostatin C ( 169 ) Penicillium sp. OUPS-79 Marine alga Polyketide P388, BSY-1, MCF-7, HCC2998, NCI-H522, DMS114, OVCAR-3, MKN1 (1.0, 2.0, 1.6, 2.0, 2.5, 1.9, 2.4, 1.7) μg/mL PTP1B inhibitor (IC 50 = 0.37 μM) [ 111 , 113 ] Penostatin D ( 170 ) Penicillium sp.…”