Anticancer Approach Inspired by the Hepatotoxic Mechanism of Pyrrolizidine Alkaloids with Glycosylated Artificial Metalloenzymes.
Michitaka KurimotoTsung-Che ChangYoshitake NishiyamaTakehiro SuzukiNaoshi DohmaeKatsunori TanakaSatoshi YokoshimaPublished in: Angewandte Chemie (International ed. in English) (2022)
Metabolic oxidation of pyrrolizidine alkaloids (PAs) from herbal and dietary supplements by cytochrome P450 produces dehydro-PAs (DHPs), which leads to toxicities. A highly reactive cation species generated from the active pyrrole ring of DHPs readily reacts with various cellular components, causing hepatotoxicity and cytotoxicity. Inspired by PA-induced hepatic damage, we developed a therapeutic approach based on a cyclization precursor that can be transformed into a synthetic DHP under physiological conditions through gold-catalyzed 5-endo-dig cyclization using a gold-based artificial metalloenzyme (ArM) instead of through metabolic oxidation by cytochrome P450. In cell-based assays, the synthesis of the DHP by a cancer-targeting glycosylated gold-based ArM substantially suppressed cell growth of the targeted cancer cells without causing cytotoxicity to untargeted cells, highlighting the potential of the strategy to be used therapeutically in vivo.
Keyphrases
- induced apoptosis
- cancer therapy
- drug induced
- hydrogen peroxide
- silver nanoparticles
- papillary thyroid
- oxidative stress
- single cell
- cell therapy
- high glucose
- high throughput
- mass spectrometry
- cell cycle arrest
- diabetic rats
- ionic liquid
- stem cells
- squamous cell
- room temperature
- squamous cell carcinoma
- endoplasmic reticulum stress
- risk assessment
- young adults
- visible light
- lymph node metastasis
- nitric oxide
- simultaneous determination