In Vitro and in Vivo Study of a Photostable Quinone Compound with Enhanced Therapeutic Efficacy against Chagas Disease.

Chagas disease, a neglected tropical disease caused by the protozoan Trypanosoma cruzi poses a significant health challenge in rural areas of Latin America. The current pharmacological options exhibit notable side effects, demand prolonged administration, and display limited efficacy. Consequently, there is an urgent need to develop drugs that are safe and clinically effective.

Hexylsilane-mediated direct amidation of amino acids with a catalytic amount of 1,2,4-triazole.

In this study, we report amino acid amidation using hexylsilane and a catalytic amount of 1,2,4-triazole. The conventional protection/deprotection method for the α-amino group of amino acids is not required. The corresponding α-amino amides were obtained in moderate to good yields with low to no racemization.

Exploratory study of oxatomide derivatives with high P2X receptor inhibitory activity.

Various oxatomide derivatives were designed and synthesized to develop novel P2X receptor (P2XR) antagonists. Evaluation for in-vitro P2XR antagonist assay showed that DPM-piperazine moiety of oxatomide was required to maintain an inhibitory activity. The structure of both alkyl chains and aromatic head groups strongly affected P2XR inhibitory activity, and the analogue, with C4-type saturated alkyl chain and a non-substituted or fluorine-substituted indole, was 7.

Synthesis and Evaluation of Quinone Derivatives for Activity against Trypanosome cruzi.

A series of quinone derivatives with a variety of side chains were synthesized. These synthetic quinone compounds were evaluated for in vitro antitrypanosomal activity against trypomastigotes and amastigotes of Trypanosoma cruzi, the causative agent of Chagas disease. Measurement of solubility of quinones and their ability to permeate cell membranes were assessed to address their possible use as oral drugs.

Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice.

Lung fibrosis is the primary pathology in idiopathic pulmonary fibrosis and is considered to result from an increase in reactive oxygen species (ROS) levels in alveolar epithelial cells. However, the exact mechanism underlying lung fibrosis remains unclear and there is no effective therapy. The hydroxyl radical (OH) has the strongest oxidizing potential among ROS.

Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription.

Metformin, which is suggested to have anti-cancer effects, activates KDM2A to reduce rRNA transcription and proliferation of cancer cells. Thus, the specific activation of KDM2A may be applicable to the treatment of cancers. In this study, we screened a food-additive compound library to identify compounds that control cell proliferation.

Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high-risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi.

Synthesis and biological evaluation of quinones derived from natural product komaroviquinone as anti-Trypanosoma cruzi agents.

Current chemotherapy drugs for Chagas' disease are insufficient due to their limited efficacy; however, anti-trypanosomal agents have recently shown promise. As such, synthetic intermediates of komaroviquinone were evaluated for anti-trypanosomal activity. Based on the results, a series of novel quinone derivatives were screened for anti-trypanosomal activity and mammalian cytotoxicity.

JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation.

The rate-limiting step in ribosome biogenesis is the transcription of ribosomal RNA, which is controlled by environmental conditions. The JmjC enzyme KDM2A/JHDM1A/FbxL11 demethylates mono- and dimethylated Lys 36 of histone H3, but its function is unclear. Here, we show that KDM2A represses the transcription of ribosomal RNA.

Catalytic asymmetric epoxidation of alpha,beta-unsaturated phosphane oxides with a Y(O-iPr)3/biphenyldiol complex.

A rare-earth-metal-catalyzed asymmetric epoxidation of alpha,beta-unsaturated phosphane oxides is described. The appropriate selection of a chiral ligand and an achiral additive is important for achieving good reactivity and enantioselectivity. A Y(O-iPr)(3)/biphenyldiol complex with an achiral phosphane oxide additive afforded beta-aryl alpha,beta-epoxy phosphane oxides in 77-99 % yield and with 96-98 % ee.

Convenient method for the addition of disulfides to alkenes.

Catalytic disulfenylation reaction of alkenes by common Lewis acids has been investigated in detail. While reactions by FeCl(3) were feasible with cycloalkenes and other simple alkenes, much faster and excellent conversions were possible by AlCl(3) even with the substrates less reactive toward FeCl(3).

Bismuth- and hafnium-catalyzed hydroamination of vinyl arenes with sulfonamides, carbamates, and carboxamides.

Catalytic intermolecular hydroamination of vinyl arenes is described. Our initial investigation revealed that a Bi(OTf)3/[Cu(CH3CN)4]PF6 system previously developed for catalytic intermolecular hydroamination of 1,3-dienes was suitable for hydroamination of a styrene with sulfonamides, but the substrate generality of this system was unsatisfactory. Several metals were screened to expand the substrate scope, and a new Hf(OTf)4/[Cu(CH3CN)4]PF6 system was determined to be highly suitable.

Mixed La-Li heterobimetallic complexes for tertiary nitroaldol resolution.

A kinetic resolution of tertiary nitroaldols derived from simple ketones is described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. By using a mixture of La-Li3-(1a)3 complex (LLB 2a) and La-Li3-(1b)3 (LLB* 2b) complex in a ratio of 2/1, chiral tertiary nitroaldols were obtained in 80-97% ee and 30-47% recovery yield.

Bismuth-catalyzed intermolecular hydroamination of 1,3-dienes with carbamates, sulfonamides, and carboxamides.

A Bi(OTf)(3)/Cu(CH(3)CN)(4)PF(6) system efficiently promoted intermolecular 1:1 hydroamination of 1,3-dienes with various carbamates, sulfonamides, and carboxamides to afford allylic amines in good yield (up to 96%). Reaction proceeded with 0.5-10 mol % catalyst loading at 25-100 degrees C (generally at 50 degrees C) in 1,4-dioxane within 24 h.

syn-selective direct catalytic asymmetric Mannich-type reactions of hydroxyketones using Y{N(SiMe3)2}3/linked-BINOL complexes.

[reaction, structure: see text] Chiral Y{N(SiMe3)2}3/linked-BINOL catalyst generated Y-enolate in situ from various hydroxyketones (R2 = aryl, heteroaryl). Beta-amino-alpha-hydroxy ketones (R1 = aryl, heteroaryl, alkenyl) were obtained syn-selectively (up to 96/4) in high ee (up to 98%) and good yield (up to 98% yield).

Lewis acid-Lewis acid heterobimetallic cooperative catalysis: mechanistic studies and application in enantioselective aza-Michael reaction.

The full details of a catalytic asymmetric aza-Michael reaction of methoxylamine promoted by rare earth-alkali metal heterobimetallic complexes are described, demonstrating the effectiveness of Lewis acid-Lewis acid cooperative catalysis. First, enones were used as substrates, and the 1,4-adducts were obtained in good yield (57-98%) and high ee (81-96%). Catalyst loading was successfully reduced to 0.

Catalytic asymmetric cyano-ethoxycarbonylation reaction of aldehydes using a YLi3 tris(binaphthoxide) (YLB) complex: mechanism and roles of achiral additives.

Full details of a catalytic asymmetric cyano-ethoxycarbonylation reaction promoted by a heterobimetallic YLi3 tris(binaphthoxide) complex (YLB 1), especially mechanistic studies, are described. In the cyanation reaction of aldehydes with ethyl cyanoformate, three achiral additives, H2O, tris(2,6-dimethoxyphenyl)phosphine oxide (3a), and BuLi, were required to achieve high reactivity and enantioselectivity (up to >99% yield and up to 98% ee). The roles of achiral additives and the reaction pathway were investigated in detail.

Heterobimetallic catalysis in asymmetric 1,4-addition of O-alkylhydroxylamine to enones.

A heterobimetallic YLi3tris(binaphthoxide) catalyst (YLB) promoted a 1,4-addition of O-methylhydroxylamine in high enantiomeric excess (up to 97% ee). Catalyst loading was reduced to as little as 0.5 mol %, still affording the 1,4-adduct in 96% yield and 96% ee.

Efficient two-step conversion of alpha,beta-unsaturated aldehydes to optically active gamma-oxy-alpha,beta-unsaturated nitriles and its application to the total synthesis of (+)-patulolide C.

[reaction: see text] An efficient two-step conversion of alpha,beta-unsaturated aldehydes into optically active gamma-oxy-alpha,beta-unsaturated nitriles is described. First, catalytic asymmetric cyanation-ethoxycarbonylation using (S)-YLi(3)tris(binaphthoxide) (YLB) afforded chiral allylic cyanohydrin carbonate. Second, a [3,3]-sigmatropic rearrangement proceeded without racemization under thermal conditions to give gamma-oxy-alpha,beta-unsaturated nitriles.