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

为了开发PTP（蛋白酪氨酸磷酸酶），合成了一个“聚焦文库”（具有“核心”结构的化合物，其可以作为磷酸模拟物与PTP的保守催化位点相互作用，并具有“各种”取代基，其可以与每种酶的独特区域相互作用）。研究了具有L-抗坏血酸作为“核心”结构的新文库的构建。我们已经开发了一种有效的方法，用于氨基甲酸酯的合成使用聚合物支撑的N-羟基琥珀酰亚胺（NHS）。使用这种方法合成了抗坏血酸-氨基甲酸酯库。氨基甲酸酯衍生物可以由6-氨基-抗坏血酸和各种醇制备，也可以由5-脱羟基-抗坏血酸和各种胺制备。对这些化合物（约80个化合物）进行了对PTP 1B（PTP）的抑制活性测试，其中有几个化合物表现出中等的抑制活性，并合成了第二代化合物库4-O-烷基化特窗酸衍生物，其中4-苄基-RK-682对乙酰肝素酶具有选择性抑制活性。4-苄基-RK-682对人纤维肉瘤HT 1060细胞的侵袭和迁移也有抑制作用。

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.