Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers.

Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a Kd value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.

Palladium-Catalyzed Carbonylative Hiyama-Denmark Reaction toward the Synthesis of Aryl Carbonyl-Containing Oxindoles.

A palladium-catalyzed domino Heck cyclization/carbonylative Hiyama-Denmark cross-coupling reaction between alkene-tethered aryl iodides and silylcarboxylic acids is presented. This reaction proceeds well without toxic carbon monoxide (CO) gas and has good functional group tolerance, providing an alternative access to carbonyl-containing oxindoles. In this transformation, silylcarboxylic acids play a dual role as a CO source and a nucleophile.

Metal- and base-free tandem sulfonylation/cyclization of 1,5-dienes with aryldiazonium salts via the insertion of sulfur dioxide.

A metal- and base-free 5-endo-trig sulfonylative cyclization between 1,5-dienes, aryldiazonium salts and SO2 (from SOgen) is presented. This method could successfully produce sulfonylated pyrrolin-2-ones in one pot with excellent regioselectivity and good-to-excellent yields. This strategy features mild reaction conditions and broad substrate scope. Moreover, a scale-up reaction and three synthetic applications demonstrate the practicality of this method. Lastly, control experiments indicate that the 5-endo-trig sulfonylative cyclization may proceed in a radical pathway.

Nickel-Catalyzed Cross-Electrophile Coupling Reactions between Allylic Acetates and gem-Difluorovinyl Tosylate.

A nickel-catalyzed cross-electrophile coupling of allylic acetates and gem-difluorovinyl tosylate is presented, which first achieves allylic gem-difluoroolefins via C(sp3)-C(sp2) cross-electrophile coupling. In addition, this protocol was performed under mild reaction conditions, affording a variety of allylic gem-difluorovinyl arenes in moderate to good yields. Moreover, both linear and branched allylic acetate could produce a linear cross-coupling product exclusively. Mechanistic studies reveal that the reaction involves two different Ni(0)/Ni(II) catalytic cycles.

Palladium-catalysed difluoroolefination of benzyl tosylates toward the synthesis of gem-difluoro-2-trifluromethyl styrene derivatives.

We have presented an efficient method to access gem-difluoro-2-trifluromethyl styrene derivatives via palladium catalysis. This method features mild reaction conditions, broad substrate scope and good product yields. Moreover, gram-scale reactions demonstrated the robustness and potential of this method. Control experiments revealed that the -CF3 group was essential to the success of this transformation. Finally, the practicality of this method was successfully proven by three synthetic applications.

Copper-Catalyzed Trifluoromethylthio-arylsulfonylation of Styrene Derivatives via the Insertion of Sulfur Dioxide.

A copper-catalyzed four-component trifluoromethylthio-arylsulfonylation between styrene derivatives, AgSCF3, aryldiazonium tetrafluoroborates, and ex situ generated sulfur dioxide (from SOgen) is presented. This reaction features mild reaction conditions, good functional group tolerance, a broad substrate scope, good yields, and excellent diastereoselectivity. Preliminary mechanistic studies revealed that a radical process might be involved in this transformation.

Copper-Catalyzed Chloro-Arylsulfonylation of Styrene Derivatives via the Insertion of Sulfur Dioxide.

A copper-catalyzed four-component chloro-arylsulfonylation of styrene derivatives with aryldiazonium tetrafluoroborates, lithium chloride, and ex-situ generated sulfur dioxide (from SOgen) is presented. This sulfonylation features good functional group compatibility, mild reaction conditions, excellent regioselectivity, and good yields. The robustness and potential of this method have also been successfully demonstrated by a gram-scale reaction. Based on experimental study, a radical-involved mechanism is proposed for the transformation.

Catalytic AgF-Initiated Intramolecular 1,3-Sulfonyl Migration of gem-Difluorovinyl Sulfonates to α,α-Difluoro-ß-ketosulfones.

A 1,3-sulfonyl migration of difluorovinyl sulfonates initiated by a catalytic amount of silver fluoride is presented. α,α-Difluoro-ß-ketosulfones were successfully prepared in excellent yields. This method features high chemoselectivity, good functional group tolerance, high atom economy, and mild, environmentally benign reaction conditions. Furthermore, mechanistic experiments indicate that this migration proceeds in an intermolecular pathway and the corresponding sulfinates are possible intermediates.

Dual Nickel-/Palladium-Catalyzed Reductive Cross-Coupling Reactions between Two Phenol Derivatives.

Cross-coupling between substrates that can be easily derived from phenols is highly attractive due to the abundance of phenols. Here, we report a dual nickel-/palladium-catalyzed reductive cross-coupling between aryl tosylates and aryl triflates; both substrates can be accessed in just one step from readily available phenols. The reaction has a broad functional group tolerance and substrate scope (>60 examples). Furthermore, it displays low sensitivity to steric effects demonstrated by the synthesis of a 2,2'-disubstituted biaryl and a fully substituted aryl product. The widespread presence of phenols in natural products and pharmaceuticals allows for straightforward late-stage functionalization, illustrated with examples such as ezetimibe and tyrosine.

Thiyl radical promoted iron-catalyzed-selective oxidation of benzylic sp3 C-H bonds with molecular oxygen.

A ligand-free iron-catalyzed method for the oxygenation of benzylic sp3 C-H bonds by molecular oxygen (1 atm) using a thiyl radical as a cocatalyst has been developed. This transformation provides a facile access to amides, esters and ketones from readily accessible corresponding amines, ethers and alkanes. It features high regioselectivity, mild oxidative conditions and excellent functional group compatibility, providing good opportunities to the site-selective functionalization of complex molecules. Preliminary mechanistic studies suggest that this reaction may not undergo a benzylic cation intermediate pathway and the carbonyl oxygen atom in the products may be derived from molecular oxygen.