A Simple Synthesis of Tetraamino-[60]Fullerene Epoxides as Potential Antitumor Drug Candidates

Amphiphilic aminated fullerenes have a broad margin of safety and significant antitumor effects. Herein, we develop a simple and versatile synthesis strategy for tetraamino-[60]fullerene epoxide (C₆₀(NR¹R²)₄O) using C₆₀Cl₆ as a precursor, which notably reduces the reaction time to less than 1 h while retaining a high yield of over 80% with both cyclic and linear secondary amine substrates even at the gram level. The molecular structure of C₆₀(NR¹R²)₄O is first validated by single-crystal diffraction, and a two-step reaction mechanism comprising nucleophilic substitution of Cl and the oxidative elimination of Cl₂ is proposed based on experimental verification and density functional theory simulation. A set of water-soluble aminated C₆₀(NR¹R²)₄O was prepared in large quantities, and in vitro antitumor evaluation unveiled the critical role that terminal primary amino moieties of C₆₀(NR¹R²)₄O play in their antineoplastic effects. This work provides an effective synthesis method for aminated C₆₀(NR¹R²)₄O, facilitating the development of fullerene-derived tumor-targeted drugs.