Lysine-Based Amphiphiles with Pyrrole, Furan and Thiophene Linkers

Abstract

The development of efficient cationic amphiphiles remains an important area in the design of nonviral systems for nucleic acid delivery. In this study, we report the synthesis of three lysine-containing lipid-like amphiphiles incorporating pyrrole, furan, and thiophene as five-membered heterocyclic linkers. The compounds share a common molecular scaffold comprising two heterocyclic linkers with a lysine-derived cationic moiety and two tetradecyl chains, while differing in the five-membered heterocyclic core. The target amphiphiles were synthesized using a four-step synthetic approach involving Cu(I)-catalyzed azide–alkyne cycloaddition, followed by Boc deprotection and anion exchange to afford compounds 6a–c as tetrahydrochloride salts. The final compounds were isolated in a 39–50% range over the final two steps. Their structures were confirmed by NMR spectroscopy and high-resolution mass spectrometry. Additional multinuclear two-dimensional NMR experiments were used to support the structural assignment of compound 6a. These amphiphiles provide new structures for further investigation of their physicochemical properties, self-assembly, nucleic acid complexation, and potential application in nonviral nucleic acid delivery.