Arene–Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis

The novel metal(II)-based complexes HA-Cu, HA-Co, and
HA-Ni with
phenanthroline, sulfamethazine, and aromatic–aromatic coupled
disulfamethazines as ligands were synthesized and characterized. HA-Cu,
HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis.
HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing
significant inhibitory effect on the growth and development of tripe-negative
breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic
effects of antiproliferation, antiangiogenesis, anti-inflammatory,
pro-apoptosis, and cuproptosis to effectively inhibited tumor survival
and development. The molecular mechanism was confirmed that HA-Cu
could downregulate the expression of key proteins in the VEGF/VEGFR2
signaling pathway and the expression of inflammatory cytokines, enhance
the advantage of pro-apoptotic protein Bax, and enforce cuproptosis
by weakening the expression of FDX1 and enhancing the expression of
HSP70. Our research will provide a theoretical and practical reference
for the development of metal-sulfamethazine and its derivatives as
chemotherapy drugs for cancer treatment.