肌醇5-磷酸酶SHIP激活剂的后功能化修饰研究摘 要：磷脂酰肌醇-3-激酶（PI3K）信号通路在许多细胞功能的调节中发挥重要作用，包括存活，粘附，运动，增殖，分化和末端细胞激活。
为确保PI3K途径的激活被适当地抑制，肌醇5-磷酸酶SHIP，s SHIP和SHIP2可以将PI-3,4,5-P 3水解成PI-3,4-P2，从而有效调控PI3K信号通路。
目前基于干预信号途径开发药物的尝试绝大多数都倾向于寻找选择性激酶抑制剂，但几乎没有努力探索小分子磷酸酶激活剂的有用性。
SHIP具有对肥大细胞和巨噬细胞活化，破骨细胞形成和再吸收功能，以及对AML和CML的负性调节剂的重要作用，使其成为极具吸引力的药物靶点。
海洋天然产物Pelorol是已经确认的选择性小分子SHIP激活剂，代表一类新的抗炎剂。
本研究旨在运用后功能化修饰方法对Pelorol及其衍生物进行结构改造，以期获得活性更好的小分子SHIP激活剂。
关键词 ：PI3K；SHIP；Pelorol；后功能化修饰Late Stage Functionalization of Inositol 5-Phosphatase SHIP ActivatorAbstract: The phosphatidylinositol-3-kinase (PI3K) signaling pathway plays an important role in the regulation of many cell functions, including survival, adhesion, movement, proliferation, differentiation, and terminal cell activation. To ensure that the activation of the PI3K pathway is appropriately inhibited, inositol 5-phosphatase SHIP, SHIP and SHIP2 can hydrolyze PI-3,4,5-P3 to PI-3,4-P2, thereby effectively regulating PI3K signaling. path. At present, the vast majority of attempts to develop drugs based on intervention signal pathways tend to look for selective kinase inhibitors. There are some recent interest in studying the therapeutic potential of phosphatase inhibitors [7], but little effort has been made to explore the usefulness of small molecule phosphatase activators. The important role of SHIP as an activation of mast cells and macrophages, the formation and reabsorption of osteoclasts and negative regulators of AML and CML, and its occurrence in hematopoietic cells alone make it an attractive drug target. The marine natural product Pelorol is a confirmed selective small molecule SHIP activator that represents a new class of anti-inflammatory agents. The purpose of this study was to use post-functional modification methods to structurally modify Pelorol and its derivatives in order to obtain a more active small molecule SHIP activator.Key Words: PI3K; SHIP; Pelorol; Late Stage Functionalization1．研究生物学背景大约50％的人类癌症含有PTEN的双等位基因失活突变，这说明磷酸酶PTEN可以阻止不受控制的细胞生长。
与PTEN功能类似，磷酸酯酶SHIP2在多种细胞类型中表达，而sSHIP仅限于干细胞，并且SHIP仅在造血（血液）细胞中被发现。
Krystal等培育了SHIP基因敲除（SHIP - / - ）的小鼠[1]。
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