A PKM2 inhibitor induces apoptosis and autophagy through JAK2 in human oral squamous cell carcinoma cells.

The enzyme pyruvate kinase M2 (PKM2) is involved in glycolysis, which plays an important role in the regulation of tumor progression. In this study, we investigated the anti-tumor activity of N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide (MTP), a PKM2 inhibitor, in oral squamous cell carcinoma (OSCC) cells. Our results showed that MTP inhibited cell growth with IC50 values of 0.

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors.

As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound , that exhibits a differential tumor-suppressive effect among an array of cancer cell lines.

Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast.

A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of β-aryl β-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral β-aryl β-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral β-amino β-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.

Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis.

The genus Flavivirus contains many important pathogens, including dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). AR-12 is a celecoxib-derived anticancer agent that possesses antiviral activity against a broad range of viruses. We pharmacologically exploited this unique activity to develop additional antiviral agents, resulting in the production of the AR-12 derivatives P12-23 and P12-34.

Direct synthesis of chiral 3-arylsuccinimides by rhodium-catalyzed enantioselective conjugate addition of arylboronic acids to maleimides.

Chiral rhodium catalysts comprising 2,5-diaryl- substituted bicyclo[2.2.1]diene ligands L1-L10 were utilized in the enantioselective 1,4-addition reaction of arylboronic acids to N-substituted maleimides.

Rhodium/chiral diene complexes in the catalytic asymmetric arylation of β-pyrazol-1-yl acrylates.

The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted β-pyrazol-1-yl (E)-tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene 2a catalyst provided the corresponding addition products in 44-98% yield and 91->99.5% ee. The method was applied to the formal synthesis of (3S)-3-aryl-3-(pyrazol-1-yl)propanoic acid 1b with agonistic activity toward the human GPR40 G-protein coupled receptor.

Enantioselective and rapid Rh-catalyzed arylation of N-tosyl- and N-nosylaldimines in methanol.

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor.

Highly enantioselective Rh-catalyzed alkenylation of imines: synthesis of chiral allylic amines via asymmetric addition of potassium alkenyltrifluoroborates to N-tosyl imines.

For the first time, simple N-tosyl aryl aldimines, prepared from the condensation of tosyl amide and aromatic aldehydes, can be used as substrates in the rhodium catalyzed 1,2-addition reaction using alkenylboron nucleophiles. In the presence of 1.5 mol % of [RhCl(1e)]2, enantioselective addition of various potassium alkenyltrifluoroborates to aryl aldimines furnished the corresponding chiral allylic amines in 73-96% yield and 72->99.

Rhodium-catalyzed asymmetric addition of arylboronic acids to β-nitroolefins: formal synthesis of (S)-SKF 38393.

An efficient enantioselective addition of an array of arylboronic acids to various β-nitrostyrenes catalyzed by a novel and reactive rhodium-diene catalyst (S/C up to 1000) was developed, providing β,β-diarylnitroethanes in good to high yields (62-99%) with excellent enantioselectivities (85-97% ee). The method was extended to 2-heteroarylnitroolefins and 2-alkylnitroolefins similarly providing the desired products with high enantioselectivities and yields. The usefulness of this method was demonstrated in the formal synthesis of the enantiomer of the dopamine receptor agonist and antagonist, SKF 38393.

A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways.

Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses.