Toll 样受体 2 (TLR2) 在检测微生物病原体相关分子模式中发挥着至关重要的作用，为疫苗和抗肿瘤治疗的佐剂提供了潜在的应用。在这里，我们展示了 CaLGL-1 及其衍生物的克级合成，这些天然产物以激活小鼠 TLR2 (EC50 = 3.2 μM) 而闻名。该合成涉及利用氧化剂促进的缩醛化的简化的六步反应序列，有效地保留了酸敏感的糖苷键，以维持化合物的功能完整性。我们的结构-活性关系研究确定 R-7d 是一种有效的人类 TLR2 激活剂。它在人 THP-1 细胞中表现出亚纳摩尔活性 (EC50 = 116 pM)，与 diprovocim (EC50 = 110 pM) 相当。实验表明，R-7d 通过 TLR2/TLR1 异二聚体而不是 TLR2/TLR6 增强 NF-kB 启动子激活。 R-7d 作为一种强大的人类 TLR2 激动剂的发现为联合疗法开辟了新的可能性。

Toll-like receptor 2 (TLR2) plays a crucial role in detecting microbial pathogen-associated molecular patterns, offering potential applications as an adjuvant for vaccines and antitumor therapies. Here, we present the gram-scale synthesis of CaLGL-1 and its derivatives, natural products known for activating mouse TLR2 (EC50 = 3.2 μM). This synthesis involves a streamlined six-step reaction sequence utilizing oxidant-promoted acetalization, effectively preserving the acid-sensitive glycosidic bond for maintaining the compounds' functional integrity. Our structure-activity relationship studies identified R-7d as a potent human TLR2 activator. It demonstrated subnanomolar activity (EC50 = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC50 = 110 pM). Experiments revealed that R-7d enhances NF-kB promoter activation through TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of R-7d as a robust human TLR2 agonist opens up new possibilities for combination therapies.