Construction of focused library and the development of protein tyrosine phosphatase inhibitor

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Aiming at developing PTP (protein tyrosine phosphatase), a "focused-library" (compounds having a "core" structure that can interact with the conserved catalytic site of PTP as a phosphate mimic and having "various" substituents that may interact with the unique region of each enzyme) was synthesized. Construction of a new library having L-ascorbic acid as a "core" structure was examined. We have already developed an efficient method for carbamate synthesis using a polymer-supported N-hydroxysuccinimide (NHS). Using this method an ascorbic acid-carbamate library was synthesized. The carbamate derivatives were prepared either from 6-amino-ascorbic acid and various alcohols, or from 5-dehydroxy-ascorbic acid and various amines. The inhibitory activity of these compounds (about 80 compounds) toward PTP1B (PTP) was tested, and several compounds showed the moderate inhibitory activity.The 4-O-alkyated tetronic acid derivatives as second generation library was synthesized, and 4-benzyl-RK-682 has been found to possess a selective inhibitory activity for heparanase. 4-Benzyl-RK-682 also inhibited the invasion and migration of human fibrosarcoma HT 1060 cells.The isobenzofuranone library was also synthesized, and among them we have found the strong PKCα activators.