Combination
of DNA Damage, Autophagy, and ERK Inhibition:
Novel Evodiamine-Inspired Multi-Action Pt(IV) Prodrugs with High-Efficiency
and Low-Toxicity Antitumor Activity
Exploring multi-targeting chemotherapeutants with advantages
over
single-targeting agents and drug combinations is of great significance
in drug discovery. Herein, we employed phytogenic evodiamine (EVO)
and conventional Pt(II) drugs to design and synthesize multi-target
EVO–Pt(IV) anticancer prodrugs (4–14). Among them, compound 10 exhibited a 118-fold
enhancement in the IC50 value compared to cisplatin and
low toxicity to normal cells. Further studies proved that 10 significantly enhanced intracellular Pt accumulation and DNA damage,
perturbed mitochondrial membrane potential, inhibited cell migration
and invasion, upregulated reactive oxygen species levels, and induced
apoptosis and autophagic cell death. Molecular docking assay revealed
that 10 fits perfectly into the extracellular signal-regulated
protein kinase (ERK)-1 pocket, which was verified to produce profound
ERK suppression. Most strikingly, compound 10 exhibited
superior in vivo antitumor efficiency and effectively attenuated systemic
toxicity. Our results emphasize that functionalizing platinum drugs
with the multi-target EVO could generate synergistically excellent
anticancer activity with low toxicity and decreased resistance, which
may represent a brand-new cancer therapy modality.