College of Chemistry, Sichuan University, Chengdu 610064, PR China.
College of Chemistry, Sichuan University, Chengdu 610064, PR China.
Bioorg Med Chem. 2024 Feb 15;100:117635. doi: 10.1016/j.bmc.2024.117635. Epub 2024 Feb 7.
Although many types of cationic lipids have been developed as efficient gene vectors, the construction of lipid molecules with simple procedures remains challenging. Passerini reaction, as a classic multicomponent reaction, could directly give the α-acyloxycarboxamide products with biodegradable ester and amide bonds. Herein, two series of novel cationic lipids with heterocyclic pyrrolidine and piperidine as headgroups were synthesized through Passerini reaction (P-series) and amide condensation (A-series), and relevant structure-activity relationships on their gene delivery capability was studied. It was found that although both of the two series of lipids could form lipid nanoparticles (LNPs) which could effectively condense DNA, the LNP derived from P-series lipids showed higher transfection efficiency, serum tolerance, cellular uptake, and lower cytotoxicity. Unlike the A-series LNPs, the P-series LNPs showed quite different structure-activity relationship, in which the relative site of the secondary amine had significant effect on the transfection performance. The othro-isomers of the P-series lipids had lower cytotoxicity, but poor transfection efficiency, which was probably due to their unstable nature. Taken together, this study not only validated the feasibility of Passerini reaction for the construction of cationic lipids for gene delivery, but also afforded some clues for the rational design of effective non-viral lipidic gene vectors.
尽管已经开发出许多类型的阳离子脂质体作为有效的基因载体，但构建具有简单程序的脂质分子仍然具有挑战性。Passerini 反应作为一种经典的多组分反应，可以直接生成具有可生物降解酯键和酰胺键的α-烷氧基酰胺产物。在此，通过 Passerini 反应（P 系列）和酰胺缩合（A 系列）合成了具有杂环吡咯烷和哌啶作为头基的两类新型阳离子脂质体，并研究了其基因传递能力的相关构效关系。结果发现，虽然这两个系列的脂质都可以形成能够有效浓缩 DNA 的脂质纳米颗粒（LNP），但源自 P 系列脂质的 LNP 表现出更高的转染效率、血清耐受性、细胞摄取率和更低的细胞毒性。与 A 系列 LNP 不同，P 系列 LNP 表现出截然不同的构效关系，其中仲胺的相对位置对转染性能有显著影响。P 系列脂质的邻位异构体具有较低的细胞毒性，但转染效率较差，这可能是由于其不稳定的性质。总之，本研究不仅验证了 Passerini 反应构建用于基因传递的阳离子脂质体的可行性，而且为合理设计有效的非病毒脂质体基因载体提供了一些线索。
