Application of gold-catalyzed hydroamination in sialic acids for the cancer-localized in vivo release of an immunotherapy drug

金催化唾液酸氢氨化在免疫治疗药物癌症局部体内释放中的应用

• 批准号: 21K05302
• 负责人: 張 宗哲
• 金额: $ 2.66万
• 依托单位: Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K05302/
• 关键词: Sialyltransferase; Prodrug; Acrolein; In vivo synthesis; Gold metal; Immunotherapy; Metal catalysis; Sialic acid; Glycoalbumin

One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. Therapies are being proposed and tested in animal models that aim to decrease sialic acid on cancer cells that are crucial for maintaining the inflammatory environment in tumors. However, sialyltransferase inhibitors that have been reported to reduce the amount of sialic acid are not selective for cancer cells and could cause side effects such as kidney dysfunction and weight loss. Recently our laboratory found that acrolein is expressed in large amounts in cancer cells. Furthermore, our laboratory has developed a prodrug that can be activated selectively by the reaction with acrolein of cancer cells. Herein, this author attempted to deliver a sialyltransferase inhibitor selectively to the cancer cells by using the [3+2] cycloaddition of azide and acrolein. A prodrug was synthesized by conjugating the hydroxyl group of the sialyltransferase inhibitor with 2, 6-diisopropylphenyl azide via a carbonyl linker. The prodrug reacts with endogenous to give a diazo compound, which subsequently cleave the linker and release of the sialyltransferase inhibitor only in cancer cells.

在癌症中普遍过表达的多糖片段之一是唾液酸，它可以通过与Siglec受体结合来诱导免疫调节特性。目前正在提出并在动物模型中测试旨在减少癌细胞上唾液酸的治疗方法，唾液酸对于维持肿瘤中的炎症环境至关重要。然而，据报道，唾液基转移酶抑制剂可以减少唾液酸的数量，但对癌细胞没有选择性，可能会导致肾功能障碍和体重减轻等副作用。最近我们实验室发现丙烯醛在癌细胞中大量表达。此外，我们的实验室已经开发出一种前药，可以选择性地与癌细胞的丙烯醛反应激活。本文作者试图通过叠氮化物和丙烯醛的[3+2]环加成，将唾液基转移酶抑制剂选择性地递送到癌细胞。通过羰基连接剂将唾液基转移酶抑制剂的羟基与2,6 -二异丙基苯基叠氮偶联，合成了前药。前药与内源性药物反应生成重氮化合物，该化合物随后切割连接体并仅在癌细胞中释放唾液基转移酶抑制剂。