Jae Du Ha

Synthesis and PTP1B inhibition of 1,2-naphthoquinone derivatives as potent anti-diabetic agents.

A new series of 1,2-naphthoquinone derivatives was synthesized by various synthetic methods and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B). 1,2-Naphthoquinone derivatives with substituent at R(4) position showed submicromolar inhibitory activity, and compound 24 demonstrated 10- to 60-fold selectivity against the tested phosphatases. Also, several 4-aryl-1,2-naphthoquinone derivatives with substituents at R(3), R(6), R(7), or/and R(8) showed submicromolar inhibitory activity and good plasma stability.

Protein Tyrosine Phosphatase 1B Inhibitors: Catechols

As most intracellular signaling takes place via cascades of phosphorylation and dephosphorylation of tyrosines, protein tyrosine phosphatases have emerged as new and promising targets. Among them, protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by dephosphorylation of key tyrosine residues within the regulatory domain of the β-subunit of the insulin receptor, thereby attenuating receptor tyrosine kinase activity. Echelby et al. have demonstrated that PTP-1B knock-out mice fed with high-fat diet showed enhanced insulin sensitivity without any adverse symptoms. Thus, PTP-1B inhibitor could potentially ameliorate insulin resistance and normalize plasma glucose and insulin without inducing hypoglycemia. Recently, small molecule inhibitors of PTP-1B as well as peptide mimetics were reported in literatures. They included catechol A, o-quinones B-D, and carboxylic acids E-G. One of the inhibitors, Ertiprotafib (G) went to clinical trial, but was discontinued in Phase II due to insufficient efficacy and dose-dependent side effects. Some catechol derivatives were discovered as hits from high-throughput screening of the library of Korea Chemical Bank. As phenolic compounds with anti-oxidant activities are known to be beneficial in the treatment of diabetes and related disorders, and catechol A and similar compounds

Formation of unnatural cyclic amino acid equivalent from the simple cyclic hydrazine

An alternative method for the synthesis of unnatural cyclic amino acid equivalent from the simple cyclic hydrazine via oxidation and cyanation was developed.