Three overlooked chemical approaches toward 3-naphthalimide amonafide N-derivatives

Three efficient strategies for derivatization of the anticancer drug candidate amonafide (Quinamed, originally AS1413) are described. Unprecedented reductive amination of aryl aldehydes, S_NAr, and addition-elimination reactions, while using readily available starting materials, give quick entry to potential libraries of novel 3-aryl, 3-benzyl N-derivatives of amonafide. The selective anticancer activity of this important DNA intercalation agent is expected to be enhanced by expanding the diversity of amonafide N-derivatives. The synthetic routes reported in this work are general and readily applicable.