Rhodium(III)-Catalyzed Conjugate Addition of ß-CF3-Enones with Quinoline N-Oxides.

The site-selective incorporation of a trifluoromethyl group into biologically active molecules and pharmaceuticals has emerged as a central topic in medicinal chemistry and drug discovery. Herein, we demonstrate the rhodium(III)-catalyzed conjugate addition of ß-trifluoromethylated enones with quinoline N-oxides, which result in the generation of ß-trifluoromethyl-ß'-quinolinated ketones. The reaction proceeds under mild conditions with complete functional group tolerance. The synthetic applicability was showcased by successful gram-scale experiments and valuable synthetic transformations of coupling products.

Transition-Metal-Free Alkylation and Acylation of Benzoxazinones with 1,4-Dihydropyridines.

The direct functionalization of N-heterocycles is a vital transformation for the development of pharmaceuticals, functional materials, and other chemical entities. Herein, the transition-metal-free alkylation and acylation of C(sp2)-H bonds in biologically relevant 2-benzoxazinones with 1,4-dihydropyridines as readily accessible radical surrogates is described. Excellent functional group compatibility and a broad substrate scope were attained. Gram-scale reaction and transformations of the synthesized adducts via Suzuki coupling with heteroaryl boronic acids demonstrated the synthetic potential of the developed protocol.

SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity.

Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth.

Synthesis of Succinimide-Linked Indazol-3-ols Derived from Maleimides under Rh(III) Catalysis.

The structural modification of N-aryl indazolols as tautomers of N-aryl indazolones has been established as a hot topic in pharmaceutics and medicinal chemistry. We herein disclose the rhodium(III)-catalyzed 1,4-addition reaction of maleimides with N-aryl indazol-3-ols, which provides the succinimide-bearing indazol-3-ol scaffolds with complete regioselectivity and a good functional group tolerance. Notably, the versatility of this protocol is demonstrated by the use of drug-molecule-linked and fluorescence-probe-linked maleimides.

Ruthenium(II)-Catalyzed Tandem C-H Allylation and [3 + 2] Dipolar Cycloaddition to Construct Bridged Tetracycles.

The ruthenium(II)-catalyzed tandem C-H allylation and intramolecular dipolar cycloaddition between azomethine imines and 2-methylidenetrimethylene carbonate is described herein. The initially formed ß-substituted allyl fragment could trigger the exotype [3 + 2] cycloaddition with the polar azomethine group, resulting in the formation of bridged tetracycles bearing a hydroxymethylene group at a bridgehead carbon center. A wide substrate scope and broad functional group compatibility were observed. The gram-scale synthesis and synthetic transformations demonstrate the synthetic utility of this process.

Site-selective and metal-free C-H nitration of biologically relevant N-heterocycles.

The site-selective and metal-free C-H nitration reaction of quinoxalinones and pyrazinones as biologically important N-heterocycles with t-butyl nitrite is described. A wide range of quinoxalinones were efficiently applied in this transformation, providing C7-nitrated quinoxalinones without undergoing C3-nitration. From the view of mechanistic point, the radical addition reaction exclusively occurred at the electron-rich aromatic region beyond electron-deficient N-heterocycle ring. This is a first report on the C7-H functionalization of quinoxalinones under metal-free conditions. In contrast, the nitration reaction readily takes place at the C3-position of pyrazinones. This transformation is characterized by the scale-up compatibility, mild reaction conditions, and excellent functional group tolerance. The applicability of the developed method is showcased by the selective reduction of NO2 functionality on the C7-nitrated quinoxalinone product, providing aniline derivatives. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.