A Simple Synthesis of Tetraamino[60]Fullerene Epoxides as Potential Antitumor 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.