Modulation of Cellular NAD Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD) levels by accelerating the oxidation of NADH to NAD, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD levels on cancer-associated thrombosis.

Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors.

Formal aromatic C-H insertion for stereoselective isoquinolinone synthesis and studies on mechanistic insights into the C-C bond formation.

Formal aromatic C-H insertion of rhodium(II) carbenoid was intensively investigated to develop a new methodology and probe its mechanism. Contrasting with the previously proposed direct C-H insertion, the mechanism was revealed to be electrophilic aromatic substitution, which was supported by substituent effects on the aromatic ring and a secondary deuterium kinetic isotope effect. Various isoquinolinones were synthesized intramolecularly via six-membered ring formation with high regio- and diastereoselectivity, while averting the common Buchner-type reaction.

Total syntheses of (-)-alpha-kainic acid and (+)-alpha-allokainic acid via stereoselective C-H insertion and efficient 3,4-stereocontrol.

Reported herein is a novel approach to the total syntheses of (-)-alpha-kainic acid and (+)-alpha-allokainic acid, where the stereochemistries on C(2), C(3), and C(4) of the pyrrolidine core were introduced efficiently and selectively. A regio- and stereoselective C-H insertion reaction was utilized to prepare the gamma-lactam as an intermediate. A Michael-type cyclization of phenylsulfone with a conjugated acetylenic ketone was developed to prepare the tricyclic ketone as a key intermediate for (-)-alpha-kainic acid.

Asymmetric intermolecular heck-type reaction of acyclic alkenes via oxidative palladium(II) catalysis.

Herein, we report an asymmetric intermolecular Heck-type reaction of acyclic alkenes by using a palladium-pyridinyl oxazoline diacetate complex under oxidative palladium(II) catalysis conditions. A premade palladium-ligand complex afforded higher enantioselectivities than a corresponding premixed palladium-ligand system, while offering enhanced asymmetric induction when compared to known intermolecular Heck-type protocols.

Oxidative palladium(II) catalysis: A highly efficient and chemoselective cross-coupling method for carbon-carbon bond formation under base-free and nitrogenous-ligand conditions.

We report herein the development of a general and mild protocol of oxygen-promoted Pd(II) catalysis resulting in the selective cross-couplings of alkenyl- and arylboron compounds with various olefins. Unlike most cross-coupling reactions, this new methodology works well even in the absence of bases, consequently averting undesired homo-couplings. Nitrogen-based ligands including dimethyl-phenanathroline enhance reactivities and offer a highly efficient and stereoselective methodology to overcome challenging substrate limitations.

Oxygen-promoted palladium(II) catalysis: facile C(sp2)-C(sp2) bond formation via cross-coupling of alkenylboronic compounds and olefins.

[reaction: see text] Oxygen-promoted Pd(II) catalysis facilitated the synthesis of conjugated dienes by cross-coupling of alkenylboronic compounds and various olefins including highly substituted alkenes and cyclohexenone. Under mild conditions, these versatile reactions were efficient and highly stereoselective.

Gamma-lactam synthesis via C-H insertion: elaboration of N-benzyl protecting groups for high regioselectivity toward the total synthesis of rolipram.

By intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides, gamma-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions. [reaction: see text]

Oxygen-promoted Pd(II) catalysis for the coupling of organoboron compounds and olefins.

Reported herein is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles. This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings.

A novel synthetic route to chiral gamma-lactams from alpha-amino acids via Rh-catalyzed intramolecular C-H insertion.

Highly functionalized gamma-lactams are key intermediates for the synthesis of numerous biologically significant natural products. We herein described the synthesis of various chiral gamma-lactams via intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides derived from alpha-amino acids, which possess various functional groups. The cyclizations were highly regio- and stereoselective to afford chiral gamma-lactam motifs in high yields.