Abstract：
Tumour-derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan-ST inhibitor (or sialidase) or systemic delivery of a non-toxic selective ST inhibitors are being pursued as potential new anti-metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP-Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral α-hydroxy-1,2,3-triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub-types. Our ST inhibitors are non-toxic and show improved synthetic accessibility and drug-likeness compared to earlier nucleoside-based ST inhibitors.
摘要：
肿瘤来源的唾液酸聚糖，在其末端带有带电的非尿糖唾液酸，在肿瘤细胞粘附和侵袭中起关键作用，以及逃避细胞死亡和免疫监视。唾液酸转移酶（ST），负责唾液酸化聚糖生物合成的酶，在癌症中高度上调，肿瘤唾液酸过度与肿瘤生长密切相关，转移和耐药性。因此,使用pan-ST抑制剂（或唾液酸酶）的靶向递送或无毒选择性ST抑制剂的全身递送对肿瘤细胞表面进行去唾液酸化，作为针对包括胰腺癌在内的多种癌症的潜在新的抗转移策略。卵巢,乳房,黑色素瘤和肺癌。在这里，我们采用分子模型来深入了解一系列选择性ST抑制剂中观察到的选择性,这些选择性ST抑制剂掺入了尿苷环代替天然供体的胞苷(CMP-Neu5Ac),并用中性α-羟基-1,2,3-三唑接头取代了经典ST抑制剂的带电磷酸二酯接头.确定新生化合物对重组人ST酶（ST3GAL1，ST6GAL1，ST8SIA2）的抑制活性，显示出对特定ST亚型的有希望的活性和选择性。与早期基于核苷的ST抑制剂相比，我们的ST抑制剂无毒，并显示出改善的合成可及性和药物相似性。
