Two-Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I poison.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

A facile approach to phenothiazinones via catalytic aerobic oxidation: discovery of an antiproliferative agent.

The production of bioactive pharmaceutical ingredients in a sustainable manner has become essential in the modern academic and industrial community. Herein, we report a chemically robust and sustainable aerobic oxidation for the synthesis of the phenothiazinone framework, using the commercially available TEMPO/HBF4/NaNO2 co-catalytic system under an ambient atmosphere. The reaction is highly efficient with broad scopes and excellent scalability. Preliminary activity screening led to the discovery of compound 3 as a potent antiproliferative agent. The green synthesis of a variety of sulfur containing heterocycles might encourage the pursuit of biologically valuable molecules in the medicinal field.

Electrochemical Synthesis of Phenothiazinone as Fluorophore and Its Application in Bioimaging.

Phenothiazinone is a promising yet underutilized fluorophore, possibly due to the lack of a general accessibility. This study reports a robust and scalable TEMPO-mediated electrochemical method to access a variety of phenothiazinones from 2-aminothiophenols and quinones. The electrosynthesis proceeds in a simple cell architecture under mild condition, and notably carbon-halogen bond in quinones remains compared to conventional methods, enabling orthogonal downstream functionalization. Mechanistic studies corroborate that TEMPO exerts a protective effect in avoiding product decomposition at the cathode. In particular, benzophenothiazinones show intriguing luminescence in both solid and solution state, and thus their photophysical properties are scrutinized in detail. Further bio-imaging of the lipid droplets in living cells highlights the considerable promise of benzophenothiazinones as fluorescent dye in the biomedical fields.