Programmed S → N Remote Cyano Migration: A Thiocyanate-Based Entry to Cyanamides and Selective Ferroptosis Inducers
Xiyan Duan, Wanjing Feng, Fengjiao Du, Can Liu, Ning Liu, Yihao Zhao, Kun Liu, Pu Liu, Yixuan Zhang, Jingze Li, Yahui Ding, Quan ZhangAbstract
Ferroptosis represents a promising strategy to overcome apoptosis-associated drug resistance, yet access to diverse and drug-like ferroptosis-inducing chemical space remains limited. Among potential scaffolds for populating this high-value space, cyanamide-bearing molecules are attractive but synthetically challenging due to the long-standing difficulty of constructing the N–CN bond. Here we disclose a thiocyanate-enabled cascade cyclization that leverages inexpensive, low-toxicity inorganic thiocyanate as an unconventional electrophilic CN surrogate. This transformation proceeds through a cascade sequence involving SCN installation, remote S → N cyano migration, and subsequent intramolecular thiazine annulation under mild, metal-free conditions. The resulting cyanamide 3,4-dihydro-2H-1,4-thiazines exhibited nanomolar ferroptosis-inducing potency; lead compounds 3b and 3c achieved IC50 values of 6.8 nM and 14 nM, respectively; and significantly suppressed tumor growth in a lung cancer PDX model.