Synthesis of Formylchromone Derivatives; Inactivators of Protein Tyrosine Phosphatase 1B

Protein tyrosine phosphatases (PTPases) represent a family of enzymes that hydrolyze phosphate moiety from phosphotyrosine residues of cellular proteins and they constitute essential components for the dynamic and precise control of the phosphorylation level of signaling proteins. Because of the importance of tyrosine phosphorylation in signal transduction, PTPases have emerged as potential targets for the treatment of a diverse of human diseases. For example, inhibition of protein tyrosine phosphatase 1B (PTP1B) might be a strategy to compensate the defective insulin sensitivity commonly observed in the patients of type II diabetes. In an effort to find potent and specific inhibitors of PTPases, we found that 3-formylchromone (4oxo-4H-[1]-benzopyran-3-carboxaldehyde, 3-formyl-4benzopyrone) derivatives 1 inactivate PTPases. Some of them were potent and selective against PTP1B and this result was reported recently. Hereby, we report the synthesis of the formylchromone derivatives. One of the synthetic strategy involves the preparation of appropriately substituted phenol derivatives 3 followed by Friedel-Crafts acylation to obtain 2-acetylphenol derivatives 7 (top line of Scheme 1). Alternatively, 7 could be obtained by acetylation prior to the introduction of the substituent R (second line of Scheme 1). The core structure was then formed by Vilsmeier-Haack reaction in which 2-acetylphenol moiety in 7 was converted to 3-formylchromone structure in the presence of POCl3 and DMF (Scheme 1). 11-13