Background: 3-Lup-20(29)-ene-3β,28-diol (betulin, BN) is a natural bioactive compound with significant synthetic and pharmacological potential. A growing body of research highlights the increasing interest in BN and its derivatives, driven by their broad biological activities (anticancer, antibacterial, anti-inflammatory, antiretroviral). However, poor bioavailability and low intracellular accumulation limit its pharmaceutical application.Methods: A promising strategy to enhance BN’s therapeutic potential is glycoconjugation. This approach improves drug bioavailability, solubility, and selectivity, particularly in cancer therapy, by leveraging cancer cells’ heightened glucose demand and overexpression of glucose transporters. Incorporating anN-heterocyclic linker, such as a 1,2,3-triazole ring, further enhances biological activity.Results: We developed an efficient method for modifying the betulin backbone at position C28 with sugar units via a (CO)CH2CH2COOH linker, based on CuAAC, yielding ten new betulin glycoconjugates with good yields and purity confirmed by spectroscopic analysis (NMR, HRMS). The potential for inhibition of cancer cell proliferation (HCT-116 human colorectal carcinoma cell line and MCF-7 human breast cancer cell line) and cytotoxicity toward normal human dermal fibroblasts (NHDF-Neo) was assessed.Conclusions: The obtained glycoconjugates exhibited higher activity against MCF-7, indicating the selectivity of their action. The development of glycoconjugates based on increased glucose demand and overexpression of its transporters could be an interesting strategy for acquiring anticancer agents, combining innovative chemical solutions with biological complexity. Such an approach may be crucial in the effective fight against cancer diseases.
背景：3-羽扇豆-20(29)-烯-3β,28-二醇（白桦脂醇，BN）是一种具有显著合成与药理学潜力的天然生物活性化合物。越来越多的研究凸显出对BN及其衍生物日益增长的兴趣，这主要源于其广泛的生物活性（抗癌、抗菌、抗炎、抗逆转录病毒）。然而，其较差的生物利用度和较低的细胞内积累限制了其药物应用。 方法：糖基化是一种提升BN治疗潜力的有前景的策略。该方法通过利用癌细胞对葡萄糖需求增加及葡萄糖转运蛋白过表达的特点，可改善药物的生物利用度、溶解度和选择性，尤其在癌症治疗中。引入N-杂环连接体（如1,2,3-三唑环）可进一步增强生物活性。 结果：我们基于CuAAC反应，开发了一种在C28位通过(CO)CH2CH2COOH连接体将糖单元修饰到白桦脂醇骨架上的高效方法，合成了十种新的白桦脂醇糖基缀合物，产率良好，并通过光谱分析（NMR、HRMS）确认了纯度。评估了这些化合物抑制癌细胞增殖（HCT-116人结直肠癌细胞系和MCF-7人乳腺癌细胞系）的潜力以及对正常人真皮成纤维细胞（NHDF-Neo）的细胞毒性。 结论：所获得的糖基缀合物对MCF-7细胞表现出更高的活性，表明其作用具有选择性。基于癌细胞葡萄糖需求增加及其转运蛋白过表达的特性开发糖基缀合物，可能是获取抗癌药物的一个有趣策略，它将创新的化学解决方案与生物复杂性相结合。这种方法可能在有效对抗癌症疾病中至关重要。
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