A natural halogenated fluoride adenosine analog 5′‐fluorodeoxy adenosine induced anticolon cancer activity in vivo and in vitro

Abstract

Adenosine (ADO) and its analogs have been introduced into the anticancer clinical trials, especial for the ADO derivatives with fluoride. The biosynthesis of fluorinase produces a fluorine-containing ADO analog 5 0 -fluorodeoxy adenosine (5 0 -FDA). The toxicity and application of 5 0 -FDA has not been evaluated, which limits the application of ADO analogs. In order to study its potential mechanism, we carried out the following experiments. In our research, 5 0 -FDA displayed good antitumor activity in colon cancer cells and two colon cancer models. As a result, 5 0 -FDA concentrationdependently inhibited the proliferation, migration, and invasion in colon cancer cells through its proapoptosis and cell cycle arrest pathway. Furthermore, 5 0 -FDA inhibited the growth of colon cancer and its pulmonary metastasis in CT26 inbred mice without affecting their body weight. It was found that 5 0 -FDA remarkably increased the protein levels of Caspase 3 and cleaved-Caspase 9 and decreased Cyclin A2 and CDK2 via the regulation of p53 signaling pathway, and increased the protein levels of Caspase 8 and cleaved-Caspase 8 which participated in apoptosis pathway. All in all, 5 0 -FDA displayed excellent therapeutic effects on colon cancer and its pulmonary metastasis. We believed that our study provided a theoretical basis for further preclinical research of 5 0 -FDA in the treatment of cancer.

Enzyme Engineering Renders Chlorinase the Activity of Fluorinase

“…Fluorinase (FlA) is currently the only enzyme found in nature that can catalyze the formation of the C–F bond from inorganic fluoride. − This enzyme utilizes S -adenosyl- l -methionine (SAM) and fluoride to generate 5′-fluoro-5-deoxyadenosine (5′-FDA) and l -methionine ( l -Met) through an S N 2 nucleophilic attack mechanism. ,, With increasing interest in organofluorine compounds, many studies have focused on engineering fluorinases. − Although the crystal structure of fluorinase has been resolved, the absence of fluoride therein has hindered the elucidation of the detailed fluorination mechanism, ,,, subsequently hampering rational engineering of FlA. Therefore, developing new enzymes with fluorination functions is increasingly needed.…”

Molecular Insights into Converting Hydroxide Adenosyltransferase into Halogenase

“…11,35,41,42 These enzymes catalyze the nucleophilic attack of halide ions on C5′ of SAM to produce 5′-XDA, an adenosine analog with important roles in the pharmaceutical field. 43 Ma et al 44 avenue for the development of adenosine analog-based anticancer drugs. In addition, SalL was also used for the synthesis of SAM analogs.…”

“…Chlorinases (SalL) are SAM-dependent halogenases. ,,, These enzymes catalyze the nucleophilic attack of halide ions on C5′ of SAM to produce 5′-XDA, an adenosine analog with important roles in the pharmaceutical field . Ma et al discovered a novel halogenated adenosine analog, 5′-bromodeoxyadenosine (5′-BrDA), which exhibited potent anticancer activity against colon cancer through multiple mechanisms, including the induction of autophagy and mitochondrial apoptosis.…”