Multi-gram scale synthesis of a bleomycin (BLM) carbohydrate moiety: exploring the antitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine (10-HCPT)
Multi-gram scale synthesis of a bleomycin (BLM) carbohydrate moiety: exploring the antitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine (10-HCPT)
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博莱霉素 (BLM) 碳水化合物部分的多克规模合成：探索附有 10-羟基喜树碱 (10-HCPT) 的 BLM 二糖的抗肿瘤有益作用
DOI：
10.1039/c8nj06191b
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发表时间：
2019
影响因子：
3.3
通讯作者：
Zhou Wen
中科院分区：
文献类型：
--
作者：
Li MaoLin;Huang Weiping;Jiang Zhilin;Shi Yonghui;Yuan Sisi;Fu Kaishuo;Chen YongJun;Zhou Li;Zhou Wen
博莱霉素（BLM）二糖的“肿瘤导向”作用已被证明是一种有前途的癌症诊断工具和靶向治疗的潜在配体。然而，这些实际应用往往受到BLM二糖缺乏的阻碍。本文中，通过TMSOTF介导的糖苷化偶联方式以43.6%的总收率（就苄基半乳糖苷而言）实现了全乙酰化BLM二糖20的有效多克合成。该合成策略的关键创新点在于，首次采用廉价的苄基半乳糖苷合成了L-古洛糖亚基3作为糖基受体，反应路线缩短，产率为73.0%;通过减少二丁基氧化锡的用量，将氨解和选择性脱乙酰化合并为一锅反应，合成了3-O-氨基甲酰基-甘露糖供体4，产率为47.2%。其次，将BLM二糖掺入非特异性模型化合物10-羟基喜树碱（10-HCPT）中形成偶联物1，与10-HCPT相比，可显著提高其抗肿瘤活性，并显示出对癌细胞和正常细胞的明显选择性。而且BLM二糖本身无细胞毒性，说明BLM二糖在解决细胞毒性药物靶向抗肿瘤治疗中的重要性和潜力。
The “tumor-seeking” role of bleomycin (BLM) disaccharide has been demonstrated to serve as a promising tool for cancer diagnosis and a potential ligand for targeted therapy. However, these practical applications are often hampered by the lack of BLM disaccharide. Herein, an efficient multi-gram synthesis of peracetylated BLM disaccharide 20 is achieved by a TMSOTF-mediated glycosidation coupling manner in 43.6% overall yield in terms of benzyl galactoside. The critical innovation of the synthetic strategy is that inexpensive benzyl galactoside was first adopted to prepare an L-gulose subunit 3 as a glycosyl acceptor, with a much shorter route in 73.0% yield, and a 3-O-carbamoyl-mannose donor 4 was achieved in 47.2% yield by lowering the amount of dibutyltin oxide, and merging aminolysis and selective deacetylation into a one-pot reaction. Next, the incorporation of BLM disaccharide into 10-hydroxycamptothecin (10-HCPT), a non-specific model compound, to form conjugate 1 could significantly improve the antitumor activity and display obvious selectivity toward cancerous and normal cells in comparison with 10-HCPT. Moreover, BLM disaccharide itself was non-cytotoxic, clearly indicating the importance and potential of BLM disaccharide in solving the targeted antitumor therapy of cytotoxic drugs.