Photocatalytic intermolecular bromonitroalkylation of styrenes: synthesis of cyclopropylamine derivatives and their evaluation as LSD1 inhibitors.

A mild and efficient method for photoredox-catalyzed bromonitroalkylation of alkenes is described herein. In this reaction, bromonitromethane serves as a source of both nitroalkyl and bromine for direct and regioselective formation of C-Br and C-C bonds from alkenes, and additional cyclization provides C-C bonds to the cyclopropylamine core as an LSD1 inhibitor.

Thio(seleno)cyano-difluoroalkylation of Alkenes Using Visible-Light Photocatalysis.

A mild and efficient three-component thio(seleno)cyano-difluoroalkylation of simple alkenes is demonstrated using an iridium(ruthenium) photocatalyst. This protocol provides a direct and regioselective installation of both C-S(Se)CN [thio(seleno)cyanation] and C-CF (difluoroalkylation) bonds.

Novel Strategy To Inhibit Transthyretin Amyloidosis via the Synergetic Effect of Chemoselective Acylation and Noncovalent Inhibitor Release.

Strategies for developing targeted covalent inhibitors (TCIs), which have the advantages of a prolonged duration of action and selectivity toward a drug target, have attracted great interest in drug discovery. Herein, we report chemoselective covalent inhibitors that specifically target lysine ε-amine groups that conjugate with an endogenous protein to prevent disease-causing protein misfolding and aggregation. These TCIs are unique because the benzoyl group is preferentially conjugated to Lys15 at the top of the T4 binding site within transthyretin (TTR) while simultaneously releasing a potent noncovalent TTR kinetic stabilizer. The potency of these covalent inhibitors is superior to tafamidis, the only FDA-approved drug for the treatment of hereditary TTR amyloidosis. In addition to investigations into the covalent modification of TTR via reverse-phase high-performance liquid chromatography, direct methods are performed to confirm and visualize the presumed covalent interaction via mass spectrometry and X-ray crystallography.

Degrader-Antibody Conjugates: Emerging New Modality.

In order to deliver chemotherapeutics more efficiently, small-molecule-drug conjugates (SMDCs) and antibody-drug conjugates (ADCs) have been synthesized and explored. These conjugates not only provide selective delivery but also improve the therapeutic index of toxins. By merging this conjugate concept with target protein degradation (TPD), the degrader-antibody conjugate (DAC) field has emerged, and clinical trials have even begun in recent years. In this Perspective, we provide the concepts, applications, and recent advances in the area of DACs.

2-Amino-1,3,4-thiadiazoles as Glutaminyl Cyclases Inhibitors Increase Phagocytosis through Modification of CD47-SIRPα Checkpoint.

Glutaminyl cyclases (QC, isoQC) convert N-terminal glutamine or glutamate into pyroglutamate (pGlu) on substrates. IsoQC has recently been demonstrated to promote pGlu formation on the N-terminus of CD47, the SIRPα binding site, contributing to the "don't eat me" cancer immune signaling of CD47-SIRPα. We developed new QC inhibitors by applying a structure-based optimization approach starting from fragments identified through library screening. Screening of metal binding fragments identified 5-(1H-benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine (9) as a potent fragment, and further modification provided 5-(1-(3-methoxy-4-(3-(piperidin-1-yl)propoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-amine (22b) as a potent QC inhibitor. Treatment with 22b in A549 and H1975 lung cancer cells decreased the CD47/αhCD47-CC2C6 interaction, indicative of the CD47/SIRPα interaction, and enhanced the increased phagocytic activity of both THP-1 and U937 macrophages.

Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.

Heat shock protein 90 (Hsp90) family proteins are molecular chaperones that modulate the functions of various substrate proteins (clients) implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain of TRAP1, believed to be a client binding region. MitoQ effectively competed with TRAP1 clients, and MitoQ treatment facilitated the identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors. The findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.

Discovery and Biological Evaluation of N-Methyl-pyrrolo[2,3-b]pyridine-5-carboxamide Derivatives as JAK1-Selective Inhibitors.

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-ß-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-ß-induced migration of HSCs at 0.25 µM in wound-healing assays.

Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models.

TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.

The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice.

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1.

As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.

A highly sensitive fluorescent probe that quantifies transthyretin in human plasma as an early diagnostic tool of Alzheimer's disease.

The development of sensitive and reliable fluorescent probes for the early diagnosis of Alzheimer's disease (AD) is highly challenging and plays an important role in achieving effective treatments. Herein, we designed and synthesized an indole-based fluorophore for TTR in human plasma, an important hallmark of AD pathogenesis. This robust and simple fluorescent method allows quantification of TTR in the complex biological matrix.

Alkene Difunctionalization Using Hypervalent Iodine Reagents: Progress and Developments in the Past Ten Years.

Hypervalent iodine reagents are of considerable relevance in organic chemistry as they can provide a complementary reaction strategy to the use of traditional transition metal chemistry. Over the past two decades, there have been an increasing number of applications including stoichiometric oxidation and catalytic asymmetric variations. This review outlines the main advances in the past 10 years in regard to alkene heterofunctionalization chemistry using achiral and chiral hypervalent iodine reagents and catalysts.

CF3-Substituted Mollugin 2-(4-Morpholinyl)-ethyl ester as a Potential Anti-inflammatory Agent with Improved Aqueous Solubility and Metabolic Stability.

Although mollugin, the main ingredient of the oriental medicinal herb Rubia cordifolia, has considerable anti-inflammatory effects, it has poor aqueous solubility as well as poor metabolic and plasma stability. To overcome these shortfalls, various mollugin derivatives have been synthesized and evaluated for their ability to inhibit U937 monocyte cell adhesion to HT-29 colonic epithelial cells in TNF-α- or IL-6-induced models of colon inflammation. The 2-(4-morpholinyl)-ethyl ester of CF3-substituted mollugin (compound 15c) showed good water solubility, improved metabolic and plasma stability, and greater inhibitory activity than mesalazine in both the TNF-α- and IL-6-induced colonic epithelial cell adhesion assays, suggesting that 15c is a potential anti-inflammatory agent.

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores.

Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.

Modulatory Functionalization of Gold Nanorods Using Supramolecular Assemblies.

Supramolecular-assembly-mediated functionalization of gold nanorods (GNRs) has been developed by reversible phase transfer between water and oils, which offers a facile method for fabricating robust GNRs with surface-charge tunability. In this regard, trimethylammonium (TMA) GNRs were initially prepared from conventional cetyltrimethylammonium bromide (CTAB) GNRs by means of a ligand-exchange reaction in the presence of an excess amount of TMA ligands. To further expand their functionality and potential applications, electrostatic assemblies of positively charged TMA-GNRs with negatively charged oleate ions were prepared. These assemblies (OA-GNRs) can undergo facile phase transfer from water to hexane. Interestingly, the reversible electrostatic assembly between the TMA and OA ions fabricated onto GNRs can be easily disrupted by treatment with HCl, which removes the OA ions from the GNRs to re-form the TMA-GNRs, which can be made soluble in aqueous media again. In addition, OA-GNRs can be further used for the synthesis of negatively charged GNRs such as 11-mercaptoundecanoic acid (MUA) GNRs, which are hard to prepare directly from CTAB-GNRs. This versatile method for phase transfer and functionalization on GNRs is expected to broaden the scope of their applications in sensing, biomedical imaging, photothermal therapies, and drug delivery systems.

Systemic optimization and structural evaluation of quinoline derivatives as transthyretin amyloidogenesis inhibitors.

Wild type transthyretin (TTR) and mutant TTR misfold and misassemble into a variety of extracellular insoluble amyloid fibril and/or amorphous aggregate, which are associated with a variety of human amyloid diseases. To develop potent TTR amyloidogenesis inhibitors, we have designed and synthesized a focused library of quinoline derivatives by Pd-catalyzed coupling reaction and by the Horner-Wadsworth-Emmons reaction. The resulting 2-alkynylquinoline derivatives, (E)-2-alkenylquinoline derivatives, and (E)-3-alkenylquinoline derivatives were evaluated to inhibit TTR amyloidogenesis by utilizing the acid-mediated TTR fibril formation. Among these quinoline derivatives, compound 14c exhibited the most potent anti-TTR fibril formation activity in the screening studies, with IC50 values of 1.49 µM against WT-TTR and 1.63 µM against more amyloidogenic V30 M TTR mutant. That is comparable to that of approved therapeutic drug, tafamidis, to ameliorate transthyretin-related amyloidosis. Furthermore, rationalization of the increased efficacy of compound 14c bearing a hydrophobic substituent, such as chloride, was carried out by utilizing in silico docking study that could focus on the region of the thyroid hormone thyroxine (T4) binding sites. Additionally, the most potent compound 14c exhibited good pharmacokinetics properties. Taken together, the novel quinoline derivatives could potentially be explored as potential drug candidates to treat the human TTR amyloidosis.

A Unified Approach to the Four Azaindoline Families by Inter-/Intramolecular Annulative Diamination of Vinylpyridines.

An operationally straightforward and metal-free inter-/intramolecular oxidative diamination of vinyl aminopyridines is a common gateway to access all four azaindoline heterocycle families. 3-Amino azaindolines are formed by the reaction of ortho-vinyl N-tosyl anilines with electron-rich amines using phenyliododiaceate (PIDA) and an iodide additive.

Oxidative inter-/intermolecular alkene diamination of hydroxy styrenes with electron-rich amines.

Doubly intermolecular alkene diamination is achieved with electron-rich, terminal alkenes through the use of a hypervalent iodine (PhI(OAc)2) reagent, iodide, and electron-rich amines. Mono- and disubstituted amines combine with electron-rich alkenes, particularly o-hydroxystyrenes, to achieve the greatest level of generality. This operationally straightforward protocol, unreliant on conventional metal-based activation, is compatible with a broad range of functional groups.

Alkene diamination using electron-rich amines: hypervalent iodine-promoted inter-/intramolecular C-N bond formation.

A combined inter-/intramolecular oxidative diamination of terminal alkenes is described that uses a hypervalent iodine oxidant and a nucleophilic amine to produce 3-aminoindolines at room temperature. This operationally straightforward and metal-free protocol is compatible with a broad range of functional groups. A mechanism involving the conversion of the amine to an electrophilic nitrogen source is advanced and used to identify a protocol effective with substoichiometric amounts of iodide and commercially available phenyl iodobenzene diacetate (PIDA) as the stoichiometric oxidant.