Combination of DNA Damage, Autophagy, and ERK Inhibition: Novel Evodiamine-Inspired Multi-Action Pt(IV) Prodrugs with High-Efficiency and Low-Toxicity Antitumor Activity

Abstract

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 IC 50 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.

Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors

“…Autophagy-associated death has served as a crucial mechanism of cell demise in cancer cells . The accumulated evidence have confirmed that ERK1/2 participated in the regulation of autophagy and autophagic cell death. , To clarify the involvement of the death mechanism in 36c -treated cancer cells, we tested the impact of 36c on autophagy in the MDA-MB-231 and RKO cells. The levels of key autophagy-associated proteins Beclin-1, LC3, and p62 were measured by western blotting.…”

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis

“…On one hand, it has been one of the most promising strategies for designing a novel next-generation anticancer metal agent by rational screening the metal ion and ligand to synthesize metal complexes; − on the other hand, the lipophilicity and anticancer activity of thiosemicarbazone compounds can be improved by modifying the hydrogen atom(s) at their N4 position with another group(s). ,− To obtain a new next-generation anticancer metal drug with high efficiency and low toxicity, we designed and synthesized a series of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds by modifying the N3 position with an alkyl group or a phenyl group and then synthesized and characterized the corresponding Ru­(III) complexes. The crystal structures of Ru­(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes ( 1b–4b ) were determined by X-ray crystallography (Figure ).…”

Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

“…Platinum­(II) drugs as the cornerstone of chemotherapies display fascinating antitumor performance in clinics by inducing serious DNA lesions. , Nevertheless, their effectiveness against metastatic cancers was rather plagued by severe side effects, drug resistance, and the immune suppressive TME. − The exploration of multifunctional platinum­(IV) hybrids by incorporating diverse functional ligands supplies a promising strategy to discover novel antimetastatic platinum drugs. − Inspired by these observations, DLT was incorporated into the platinum­(IV) system for the first time in this work with the aim of exploring novel platinum drugs with potent antiproliferative and antimetastatic properties.…”