A small molecule compound 759 inhibits the wnt/beta-catenin signaling pathway via increasing the Axin protein stability.

Wnt/ß-catenin signaling plays important role in cancers. Compound 759 is one of the compounds previously screened to identify inhibitors of the Wnt/ß-catenin pathway in A549 cells [Lee et al. in Bioorg Med Chem Lett 20:5900-5904, 2010]. However, the mechanism by which Compound 759 induces the inhibition of the Wnt/ß-catenin pathway remains unknown. In our study, we employed various assays to comprehensively evaluate the effects of Compound 759 on lung cancer cells. Our results demonstrated that Compound 759 significantly suppressed cell proliferation and Wnt3a-induced Topflash activity and arrested the cell cycle at the G1 stage. Changes in Wnt/ß-catenin signaling-related protein expression, gene activity, and protein stability including Axin, and p21, were achieved through western blot and qRT-PCR analysis. Compound 759 treatment upregulated the mRNA level of p21 and increased Axin protein levels without altering the mRNA expression in A549 cells. Co-treatment of Wnt3a and varying doses of Compound 759 dose-dependently increased the amounts of Axin1 in the cytosol and inhibited ß-catenin translocation into the nucleus. Moreover, Compound 759 reduced tumor size and weight in the A549 cell-induced tumor growth in the in vivo tumor xenograft mouse model. Our findings indicate that Compound 759 exhibits potential anti-cancer activity by inhibiting the Wnt/ß-catenin signaling pathway through the increase of Axin1 protein stability.

Evolutionary Progress of Silica Aerogels and Their Classification Based on Composition: An Overview.

Aerogels are highly porous materials with fascinating properties prepared using sol-gel chemistry. Due to their unique physical and chemical properties, aerogels are recognized as potential candidates for diverse applications, including thermal insulation, sensor, environmental remediation, etc. Despite these applications, aerogels are not routinely found in our daily life because they are fragile and have highly limited scale-up productions. It remains extremely challenging to improve the mechanical properties of aerogels without adversely affecting their other properties. To boost the practical applications, it is necessary to develop efficient, low-cost methods to produce aerogels in a sustainable way. This comprehensive review surveys the progress in the development of aerogels and their classification based on the chemical composition of the network. Recent achievements in organic, inorganic, and hybrid materials and their outstanding physical properties are discussed. The major focus of this review lies in approaches that allow tailoring of aerogel properties to meet application-driven requirements. We begin with a brief discussion of the fundamental issues in silica aerogels and then proceed to provide an overview of the synthesis of organic and hybrid aerogels from various precursors. Organic aerogels show promising results with excellent mechanical strength, but there are still several issues that need further exploration. Finally, growing points and perspectives of the aerogel field are summarized.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest.

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (GI50 = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of DGG200064 as a novel oral anti-colorectal cancer drug.

Traceless Solid-Phase Synthesis of 7-Aminothiazolo[4,5-d]pyrimidine-Based Library via Dimroth Rearrangement.

Thiazolo[4,5-d]pyrimidine is one of the purine isosteres that possesses a variety of pharmaceutical activities and is an attractive scaffold for drug discovery. In this work, a novel protocol for the synthesis of 7-aminothiazolo[4,5,-d]pyrimidine scaffold libraries on solid support has been developed using a traceless linker. Dimroth rearrangement afforded the desired intermediate with a fused heterocyclic thiazolo[4,5,-d]pyrimidine core skeleton. To diversify the synthesized library, three types of building blocks were introduced to the resin-bound thiazolo[4,5,-d]pyrimidine through N-acylation, N-alkylation, and nucleophilic substitution with amines during cleavage from the resin. The synthesized compounds were produced in seven steps with overall yields of 11-48%. Additionally, physicochemical properties, as well as drug-likeness of the library, were calculated.

Heterocycles as a Peptidomimetic Scaffold: Solid-Phase Synthesis Strategies.

Peptidomimetics are a privileged class of pharmacophores that exhibit improved physicochemical and biological properties. Solid-phase synthesis is a powerful tool for gaining rapid access to libraries of molecules from small molecules to biopolymers and also is widely used for the synthesis of peptidomimetics. Small molecules including heterocycles serve as a core for hundreds of drugs, including peptidomimetic molecules. This review covers solid-phase synthesis strategies for peptidomimetics molecules based on heterocycles.

DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer.

Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats.

Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5-5 mg/kg, the terminal half-life (i.e., 2.54-2.80 h), systemic clearance (i.e., 691-865 mL/h/kg), and steady state volume of distribution (i.e., 2040-3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9-57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.

A novel sphingosylphosphorylcholine and sphingosine-1-phosphate receptor 1 antagonist, KRO-105714, for alleviating atopic dermatitis.

BACKGROUND: Atopic dermatitis (eczema) is a type of inflammation of the skin, which presents with itchy, red, swollen, and cracked skin. The high global incidence of atopic dermatitis makes it one of the major skin diseases threatening public health. Sphingosylphosphorylcholine (SPC) and sphingosine-1-phosphate (S1P) act as pro-inflammatory mediators, as an angiogenesis factor and a mitogen in skin fibroblasts, respectively, both of which are important biological responses to atopic dermatitis. The SPC level is known to be elevated in atopic dermatitis, resulting from abnormal expression of sphingomyelin (SM) deacylase, accompanied by a deficiency in ceramide. Also, S1P and its receptor, sphingosine-1-phosphate receptor 1 (S1P1) are important targets in treating atopic dermatitis. RESULTS: In this study, we found a novel antagonist of SPC and S1P1, KRO-105714, by screening 10,000 compounds. To screen the compounds, we used an SPC-induced cell proliferation assay based on a high-throughput screening (HTS) system and a human S1P1 protein-based [35S]-GTPγS binding assay. In addition, we confirmed the inhibitory effects of KRO-105714 on atopic dermatitis through related cell-based assays, including a tube formation assay, a cell migration assay, and an ELISA assay on inflammatory cytokines. Finally, we confirmed that KRO-105714 alleviates atopic dermatitis symptoms in a series of mouse models. CONCLUSIONS: Taken together, our data suggest that SPC and S1P1 antagonist KRO-105714 has the potential to alleviate atopic dermatitis.

Traceless solid-phase synthesis and ß-turn propensity of 1,3-thiazole-based peptidomimetics.

The design and solid-phase synthesis of 1,3-thiazole-based peptidomimetic molecules is described. The solid-phase synthesis was based on the utilization of a traceless linker strategy. The synthesis starts from the conversion of chloromethyl polystyrene resin to the resin with a sulfur linker unit. The key intermediate 4-amino-thiazole-5-carboxylic acid resin is prepared in three steps from Merrifield resin. The amide coupling proceeded at the C4 and C5 positions via an Fmoc solid-phase peptide synthesis strategy. After cleavage, the final compounds were obtained in moderate yields (average 9%, 11-step overall yields) with high purities (≥87%). Geometric measurements of Cα distances and dihedral angles along with an rmsd of 0.5434 for attachment with Cα of the ß-turn template suggest type IV ß-turn structural motifs. Additionally, the physicochemical properties of the molecules have been evaluated.

Design and Solid-Phase Parallel Synthesis of 2,4,5-Trisubstituted Thiazole Derivatives via Cyclization Reaction with a Carbamimidothioate Linker.

Preparation of 2,4,5-trisubstituted thiazole derivatives via a new solid-phase synthetic route has been conducted in this study. The synthetic route begins with the synthesis of a core skeleton 2,4-diamino(thiazol-5-yl)-substituted phenylmethanone resin obtained through a cyclization reaction with a carbamimidothioate linker. The core skeleton was substituted with diverse building blocks such as amines, alkyl halides, and acid chlorides. The products were cleaved from the solid support via a TFA/CH2Cl2 cleavage cocktail. Overall, the strategy permits the incorporation of three points of diversity into the thiazole ring system with good overall yields ( Lee , T. ; et al. J. Comb. Chem. 2009 , 11 ( 2 ), 288 - 293 ). Finally, the library of 2,4,5-trisubstituted thiazole derivatives showed oral bioavailability through calculation of the physicochemical properties.

Synthesis of 2-Amino-5-Carboxamide Thiazole Derivatives via Dehydrative Cyclization of Thiourea Intermediate Resin on Solid Phase.

In this study, we synthesized 2-amino-5-carboxamide thiazole derivatives on solid phase. The synthesis of the library starts with the reductive amination of the 4-formyl-3-methoxy phenoxy resin to prevent isomer formation. The dehydrative cyclization of thiourea intermediate resin, which is the key step in the synthetic process, was successfully synthesized using α-bromoketone in the presence of the DMF so as to afford 2-amino-5-carboxylate thiazole resin. The resulting resin is coupled with various amines. Finally, the 2-amino-5-carboxamide thiazole resin was cleaved from the polymer support using a TFA and DCM cocktail. The physicochemical properties of the proposed 2-amino-5-carboxamide thiazole derivatives were calculated and showed potential to be an reasonable oral bioavailability drug properties as determined by Lipinski's Rule.

Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus.

Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1-139 a.a)-p53 complex to the autophagosome, through TGase 2 (472-687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81-116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53-TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81-116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.

Current Parallel Solid-Phase Synthesis of Drug-like Oxadiazole and Thiadiazole Derivatives for Combinatorial Chemistry.

Solid-phase organic synthesis is a powerful tool in the synthesis of small organic molecules and building of libraries of compounds for drug discovery. Heterocyclic compounds are important components of the drug discovery field as well and serve as a core for hundreds of marketed drugs. In particular, oxadiazole and thiadiazole cores are compounds of great interest due to their comprehensive biological activities and structural features. Therefore, a plethora of oxadiazole and thiadiazole synthesis methodologies have been reported to date, including solution and solid-phase synthesis methodologies. In this review, we concentrate on and summarize solid-phase synthetic approaches of the oxadiazole and thiadiazole derivatives.

Construction of Druglike 2-Amido Benzo[ d]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase.

A 2-amido benzo[ d]imidazole library has been constructed by solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo[ d]imidazole resin through desulfurative cyclization of thiourea resin using 2-chloro-1,3-dimethylimidazolinium chloride and N, N-diisopropylethylamine in dichloromethane (DCM), and the resin is then functionalized by acylation at the 2-amine position to afford 2-amidobenzo[ d]imidazole resin. In the case of 2-amidobenzo[ d]imidazole resin having a p-I or m-NO2, the resin was further functionalized by Suzuki/Sonogashira-coupling ( p-I) and reduction to the primary amine ( m-NO2) followed by acylation. Finally, the functionalized 2-amido-benzo[ d]imidazole resin was cleaved from the polymer support by treatment with a cocktail of trifluoroacetic acid and DCM. As a result, we obtained 2-amidobenzo[ d]imidazole analogues in high yield and good purities.

Construction of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Library with a High Level of Skeletal Diversity Based on Branching Diversity-Oriented Synthesis on Solid-Phase Supports.

An efficient solid-phase synthetic route for the construction of 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries based on branching diversity-oriented synthesis (DOS) has been developed in this study. The core skeleton resins, 1,3,4-oxadiazole and 1,3,4-thiadiazole, were obtained through desulfurative and dehydrative cyclizations of thiosemicarbazide resin, respectively. Various functional groups have been introduced to the core skeleton resins, such as aryl, amine, amide, urea, thiourea, and an amino acid. Most of the libraries were purified by simple trituration without extraction or column chromatography after cleavage of the products from the solid-supported resin. As a result, we obtained high yields of pure 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives (total numbers = 128). Finally, we confirmed the drug-like properties of our library by calculation of physicochemical properties, displays of the skeletal diversities of the library in 3D-space, and occupation of a broad range of areas by their functional groups.

Unveiling the photophysical and morphological properties of an acidochromic thiophene flanked dipyrrolopyrazine-based chromophore for optoelectronic application.

A series of dipyrrolopyrazine (DPP) based chromophores featuring thiophene and varied donor (N,N-dimethylamine, NH2, OMe) and acceptor (CF3, CN, NO2) appendages have been synthesized. The structures and properties of the chromophores were investigated by absorption spectroscopy, electrochemistry, differential scanning calorimetry, and thermogravimetric analysis. X-ray crystallographic analysis indicates a planar geometry for the molecule 7g. Surface morphological studies reveal the formation of microrods and nanorods. The acidochromic behavior of the chromophore which shows a prominent red-shift in the absorption spectra owing to the protonation of the pyrazine segment provides a valuable opportunity to assess the sensory response. Acid dependent spectral changes could be successfully applied to detect pH in biological fluids and acid impurities in solvents.

Synthesis of 2-Alkoxy/Thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a Phase-Based, Chemoselective Reaction.

2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[d]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[d]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space.

Solid-Phase Parallel Synthesis of N-Substituted-2-aminothiazolo[4,5-b]pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated Resin with o-Bromo-2-Aminopyrazines.

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin 2 with o-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. The physicochemical properties and the polar surface areas of synthesized compounds were evaluated.

Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin.

A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using p-TsCl as the desulfurative agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido-5-amino-1,3,4-thiadiazole resin, respectively. Finally, these functionalized 1,3,4-thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4-thiadiazole analogs in high yields and purities. The 1,3,4-thiadiazole analogs show a different distribution of physicochemical and biological properties compared with our previously constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a range of orally available drug properties.