ortho-Substituted lipidated Brartemicin derivative shows promising Mincle-mediated adjuvant activity

摘要

At present, TDB is the preferred Mincle agonist for adjuvant development due to its structural simplicity and the promising results achieved with the CAF01 liposome system. Due to the success of TDB, there has been much interest in the development of additional Mincle agonists that have enhanced activity. We recently reported on the synthesis of several lipi- dated Brartemicin derivatives (e.g., 4 [C18dMeBrar] and 5c [p-OC_(18)]) that possess potent Mincle agonist activity and are available in five steps from commercially available materials. In addition, our lead agonist, 4 (C18dMeBrar), demonstrated potent Th1 adjuvant activity, which was greater than that of TDB. In this work, we have prepared an additional series of lipidated Brartemicin analogues that feature structural modifications such as alterations to the positioning of the lipophilic chain on the aromatic diesters, the total number of lipophilic chains, the position of the aromatic group on the lipid-chain, and the type of linkage incorporated between the aromatic group and the lipid-tail. The target glycolipids were efficiently prepared from commercially available materials (4-5 steps, longest linear sequence) and in overall yields of 5-46%. While all the synthesised ligands demonstrated an ability to signal through mMincle and hMincle, the o-substituted derivative 5a (o-OC_(18)) and, to a lesser extent, the m,m-substituted derivative 5d (m,m-bis[OC_(18)]) induced potent inflammatory responses in both BMDMs and human monocytes and are therefore, potent Mincle ligands that possess superior activity to TDB, 5c (p-OC_(18)), and C18dMeBrar (4).