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. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2–6 were isolated from the entomogenous fungus Isaria fumosorosea. The structures of 2–6 were elucidated by extensive spectroscopic analysis. Fumosorinone A (1) and beauvericin (6) showed significant PTP1B inhibitory activity with IC50 value of 3.24 μM and 0.59 μM.
Highlights
Tyrosine phosphorylation and dephosphorylation are crucial elements in eukaryotic signal transduction
The NMR data of 1 were similar to those of militarinone C [7], suggesting that 1 (Figure 1) had a same pyrrolidinedione skeleton deduced from the HMBC correlations (H-5/C-2, C-3, and C-4) and a p-hydroxybenzyl group supported by the 1 H-1 H COSY cross-peaks (H-20 /H-30 and H-50 /H-60 ) and HMBC correlations (H-6/C-20, C-60 ; H-20, H-60 /C-40 ) (Figure 2)
The linkage of the p-hydroxybenzyl group with C-5 was established by the 1 H-1 H COSY cross-peak of H-5/H-6 and HMBC correlation from H-6 to C-4
Summary
Tyrosine phosphorylation and dephosphorylation are crucial elements in eukaryotic signal transduction. More recent evidence has suggested protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of the insulin signaling pathway [2]. Several ‘classical’ protein tyrosine phosphatases are attractive therapeutic targets, including PTP1B for obesity and type II diabetes; as well as SHP2 for cancer and Lyp for rheumatoid arthritis [3]. Despite the research efforts in academia and industry over the past decade, there are very few PTPase inhibitors that have been advanced into clinical trials [4]. Inhibition of PTP1B can be considered as an attractive approach for the design of new therapeutic agents for the treatment of type II diabetes and for new antitumor drugs. Very few inhibitors have been isolated from microorganisms, insect pathogenic fungi [3]
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