Programmed S → N Remote Cyano Migration: A Thiocyanate-Based Entry to Cyanamides and Selective Ferroptosis Inducers.

Authors

Xiyan Duan, Wanjing Feng, Fengjiao Du, Can Liu, Ning Liu, Yihao Zhao, Kun Liu, Pu Liu, Yixuan Zhang, Jingze Li, Yahui Ding, Quan Zhang

Published in

ACS central science. Volume 12. Issue 8. Pages 1237-1245. Aug 26, 2026. Epub Aug 06, 2026.

Abstract

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.

PMID:
42666827
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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