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Molecular design of anticancer drug, α-NaGalase inhibitors for immunopotentiation

抗癌药物、免疫增强α-NaGalase抑制剂的分子设计

基本信息

批准号：
10672090
负责人：
HORI Hitoshi
金额：
$ 2.11万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

It was supposed as one of the mechanisms for immuno-suppression in cancer patients that macrophage activating factor (Gc MAF) could not be produced from a precursor, serum vitamin D-binding protein (Gc protein) due to deglycosylation by a-N-acetyl galactosaminidase (α-NaGalase). It was reported that α-NaGalase increased in cancer patients serum (Yamamoto, N. et al., 1998). To develop a immuno modulator of cancer therapy, the mechanism of immuno-suppression was defined by characterization of α-NaGalase in various tumor cells and α-NaGalase inhibitors was designed and synthesized as immuno potentiator.1) α-NaGalase activities in tumor cell lysates from Hep G2 and HCT116 cells and normal cell lysates from Chang liver cell and isolated rat hepatocytes were measured. A high specific activity of a-NaGalase was found in tumor cell lines compare to normal cells. Because α-NaGalase deglycosylated exo-type substrate specifically, it was necessary to reinvestigate the deactivation mechanism of GcMAF by a-NaGalase.2) Azasugar derivatives introduced spィイD12ィエD1 carbon to control a torsional angle between hydroxyl groups were designed and synthesized as a α-NaGalase inhibitor and an immunopotentiator, because a sugar-shaped alkaloid, swainsonine, was a α-mannosidase inhibitor and an immunopotentiator. Their activities of α-NaGalase inhibition and macrophage activation are now under investigation.

巨噬细胞活化因子（macrophage activating factor，Gc MAF）是一种前体蛋白，血清中的维生素D结合蛋白（vitamin D binding protein，Gc protein）被α-N-乙酰氨基半乳糖酶（α-NaGalase）去糖基化而不能产生，这被认为是肿瘤患者免疫抑制的机制之一。据报道，α-NaGalase在癌症患者血清中增加（Yamamoto，N.例如，1998年）。为开发肿瘤免疫调节剂，通过对α-NaGalase在多种肿瘤细胞中的特性分析，明确其免疫抑制机制，设计并合成了α-NaGalase抑制剂作为肿瘤免疫增强剂。1）测定了Hep G2和HCT 116肿瘤细胞裂解液、Chang肝细胞和大鼠肝细胞裂解液中α-NaGalase的活性。与正常细胞相比，在肿瘤细胞系中发现α-NaGalase的高比活性。由于α-NaGalase具有去糖基化外切型底物的特异性，因此有必要重新研究α-NaGalase对GcMAF的失活机理。2）利用糖型生物碱苦马豆素对α-甘露糖苷酶的抑制作用和免疫增强作用，设计并合成了一种通过引入β-D_（12）β-D_（1）碳原子来控制羟基间扭转角的氮杂糖衍生物。其α-半乳糖醛酸酶抑制活性和巨噬细胞活化活性正在研究中。