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, SNAr, 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.