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

通常在癌症中过表达的聚糖部分之一是唾液酸，其可以通过与Siglec受体结合来诱导免疫调节特性。正在提出并在动物模型中测试旨在减少癌细胞上的唾液酸的治疗方法，这些唾液酸对于维持肿瘤中的炎症环境至关重要。然而，据报道可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，并可能导致副作用，如肾功能障碍和体重减轻。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。在此，作者尝试通过使用叠氮化物和丙烯醛的[3+2]环加成将唾液酸转移酶抑制剂选择性地递送至癌细胞。通过将唾液酸转移酶抑制剂的羟基与2，6-二异丙基苯基叠氮通过羰基连接体缀合来合成前药。前体药物与内源性药物反应，得到重氮化合物，随后裂解接头并仅在癌细胞中释放唾液酸转移酶抑制剂。

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.