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

在癌症中普遍过度表达的糖链之一是唾液酸，它可以通过与Siglec受体结合来诱导免疫调节特性。正在提出治疗方法，并在动物模型中进行测试，旨在减少癌细胞上的唾液酸，唾液酸对维持肿瘤中的炎症环境至关重要。然而，据报道可以减少唾液酸量的唾液酸转移酶抑制剂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，我们的实验室发现丙烯醛在癌细胞中大量表达。此外，我们的实验室还开发了一种前药，可以通过与癌细胞的丙烯醛反应选择性地激活。在这里，作者试图通过叠氮和丙烯醛的[3+2]环加成，选择性地将唾液酸基转移酶抑制剂输送到癌细胞。将唾液酸基转移酶抑制剂的羟基与2，6-二异丙基苯叠氮化物通过羰基连接，合成了前药。前药与内源性反应生成重氮化合物，重氮化合物随后切割连接物，仅在癌细胞中释放唾液酸基转移酶抑制剂。

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.