1. Anticancer Approach Inspired by the Hepatotoxic Mechanism of Pyrrolizidine Alkaloids with Glycosylated Artificial Metalloenzymes
- Author
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Kurimoto, Michitaka, Chang, Tsung‐che, Nishiyama, Yoshitake, Suzuki, Takehiro, Dohmae, Naoshi, Tanaka, Katsunori, Yokoshima, Satoshi, Kurimoto, Michitaka, Chang, Tsung‐che, Nishiyama, Yoshitake, Suzuki, Takehiro, Dohmae, Naoshi, Tanaka, Katsunori, and Yokoshima, Satoshi
- Abstract
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.
- Published
- 2023