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Due to the diversity of structure and composition and the unique coordination environment, nitride materials enable the doped activator ions to possess compelling luminescence characteristics, such as rich emission colors, favorable stability and tunable emission spectra. Here, novel SrLuSi

The inhibition of human ornithine δ-aminotransferase (hOAT) is a potential therapeutic approach to treat hepatocellular carcinoma. In this work, (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6) was identified as a potent mechanism-based inactivator of hOAT while showing excellent selectivity over other related aminotransferases (e.g., GABA-AT). An integrated mechanistic study was performed to investigate the turnover and inactivation mechanisms of 6. A monofluorinated ketone (M10) was identified as the primary metabolite of 6 in hOAT. By soaking hOAT holoenzyme crystals with 6, a precursor to M10 was successfully captured. This gem-diamine intermediate, covalently bound to Lys292, observed for the first time in hOAT/ligand crystals, validates the turnover mechanism proposed for 6. Co-crystallization yielded hOAT in complex with 6 and revealed a novel noncovalent inactivation mechanism in hOAT. Native protein mass spectrometry was utilized for the first time in a study of an aminotransferase inactivator to validate the noncovalent interactions between the ligand and the enzyme; a covalently bonded complex was also identified as a minor form observed in the denaturing intact protein mass spectrum. Spectral and stopped-flow kinetic experiments supported a lysine-assisted E2 fluoride ion elimination, which has never been observed experimentally in other studies of related aminotransferase inactivators. This elimination generated the second external aldimine directly from the initial external aldimine, rather than the typical E1cB elimination mechanism, forming a quinonoid transient state between the two external aldimines. The use of native protein mass spectrometry, X-ray crystallography employing both soaking and co-crystallization methods, and stopped-flow kinetics allowed for the detailed elucidation of unusual turnover and inactivation pathways.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the leading cause of death among people with cirrhosis. HCC is typically diagnosed in advanced stages when tumors are resistant to both radio- and chemotherapy. Human ornithine aminotransferase (hOAT) is a pyridoxal-5′-phosphate (PLP)-dependent enzyme involved in glutamine and proline metabolism. Because hOAT is overexpressed in HCC cells and a contributing factor for the uncontrolled cellular division that propagates malignant tumors (Ueno, A. et al., J. Hepatol. 2014, 61, 1080–1087), it is a potential drug target for the treatment of HCC. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic acid (BCF(3)) has been shown in animal models to slow the progression of HCC by acting as a selective and potent mechanism-based inactivator of OAT (Zigmond et al., ACS Med. Chem. Lett. 2015, 6, 8, 840–844). Previous studies have shown that the BCF(3)-hOAT reaction has a bifurcation in which only 8% of the inhibitor inactivates the enzyme while the remaining 92% ultimately acts as a substrate and undergoes hydrolysis to regenerate the active PLP form of the enzyme. In this manuscript, the rate-limiting step of the inactivation mechanism was determined by stopped-flow spectrophotometry and time-dependent (19)F-NMR experiments to be the decay of a long-lived external aldimine species. A crystal structure of this transient complex revealed both the structural basis for fractional irreversible inhibition and the principal mode of inhibition of hOAT by BCF(3), which is to trap the enzyme in this transient but quasi-stable external aldimine form.

Two new steroidal glycosides 1 and 2 have been isolated from the n-butanol extract portion of Anemarrhena asphodeloides Bunge (A.asphodeloides), a widely used plant as Traditional Chinese Medicine. Their structures have been confirmed through a variety of analytic approaches including 1D and 2D-NMR spectroscopic techniques as well as mass spectrometry data. Moreover, cytotoxic activity evaluation demonstrated that compound 2 exhibited micromole level cytotoxic effects against A549 and Hela cancer cells.

A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.

Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues 4d, 4e, and 7b bearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1. Compound 4d exhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that 4d selectively increases acetylated tubulin levels in vitro and elicits an immune response through down-regulating cytokine IL-10. A preliminary in vivo efficacy study indicates that 4d possesses improved capability to inhibit melanoma tumor growth and that this effec...

The flowers of Polianthes species were collected in the Thai Nguyen city, Viet Nam. Their volatile oil extracts were obtained via supercritical CO2 extraction and chemical compositions of the volatile oil part were subsequently analysed by GC-FID and GC/MS systems. Some major chemical compositions of volatile oil were identified as methyl 2-amino benzoate, isoeugenol, 1-Eicosene, indole, 5-octadecene, benzylbenzoate, diisobutylphthalate, 1-nonadecene, trans-farnesol. The chemical compositions of volatile oil of Polianthes sessiliflora (P. sessiliflora) and Polianthes longiflora (P. longiflora) species were being reported for the first time.The activities of total volatile oil extract of the Polianthes genus flowers against HeLa, A459, and Hep-2 cancer cell lines were evaluated.

[Image: see text] Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as HDAC6 plays a crucial regulatory role in axonal transport deficits, protein aggregation, as well as oxidative stress. In this work, we provide new insights into this HDAC6i by investigating the molecular basis of its interactions with HDAC6 through X-ray crystallography, determining its functional capability to elevate the levels of acetylated α-tubulin in vitro and in vivo, correlating PK/PD profiles to determine effective doses in plasma and brain, and finally assessing its therapeutic potential toward psychiatric diseases through use of the SmartCube screening platform.

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease. ispartof: ACS CHEMICAL NEUROSCIENCE vol:10 issue:3 pages:1679-1695 ispartof: location:United States status: published

[Image: see text] Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed with the C-terminal catalytic domain of HDAC6. When compared with the structure of a mercaptoacetamide bound to the class I isozyme HDAC8, different interactions are observed with the conserved tandem histidine pair in the active site. These differences likely contribute to the selectivity for inhibition of HDAC6, an important target for cancer chemotherapy and the treatment of neurodegenerative disease.

[Image: see text] The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C(4) position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC(50) = 20/376/204/46 nM) and mTOR (IC(50) = 189 nM), potent functional suppression of AKT phosphorylation (IC(50) = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C(4) sulfone chain and a fluorine on the C(6) aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform-selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first-generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell-cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole-based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1-3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl cells. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation.

A one-pot procedure was developed for the synthesis of isoindolin-1-imine derivatives by a simple three-component condensation of 2-cyanobenzaldhyde, ammonium acetate, and 4-hyroxycoumarin derivatives or 1,3-dicarbonyl compounds or 4-hydroxyquinolin-2(1 H )-one in ethanol under reflux for 20–60 min with excellent yields. The advantages of this procedure are operational simplicity, excellent yields, and short reactive time, without catalyst, easy workup, and green environmental impact.

A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure–activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.

Multidrug resistance (MDR) to anticancer drugs is a major obstacle to successful chemotherapy in the treatment of cancers. Identification of natural compounds capable of circumventing MDR with minimal adverse side effects is an attractive goal. Here, we found that H6, a gypenoside aglycon from Gynostemma pentaphyllum, displayed potent anti-MDR activity. Average resistant fold (RF) of H6 is 1.03 and 1.04 in KB/VCR and MCF-7/ADR cells compared to their parental cells. H6 alone ranging from 2 μmol/l to 40 μmol/l (μM) did not display a significant anti-proliferative effect on KB/VCR cells and other cells, while the compound at these concentrations enhanced the cytotoxicity of vincristine (VCR) to KB/VCR cells. H6 showed a significant synergistic effect in combination with VCR. By quantification of sub-G(1) fraction cells, H6 also enhanced the VCR-induced apoptosis in a dose-dependent manner. The short time treatment with H6 increased the intracellular accumulation of rhodamine 123 (Rho123) and 5(6)-carboxyfluorescein diacetate (CFDA) in KB/VCR cells. Further studies showed that H6 treatment resulted in the decrease of the RNA transcript level of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). H6 inhibited the function of P-gp by stimulating P-gp ATPase activity and decreased MRP1 expression with a blockade of STAT3 phosphorylation. These findings suggest that H6, a multi-targets reversal agent with no significant toxic effect, may be a potential candidate to circumvent the P-gp and MRP1-mediated MDR.

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.

Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that "pan-HDAC inhibitors" may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery.

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure–activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.

A facile and high-yielding route for the synthesis of solasodine from diosgenin is devised. Ring opening of steroidal spiroketal under mild conditions with trifluoroacetyl trifluoromethanesulfonate (TFAT) provides an applicable protocol to prepare key intermediates 4 or 3-Ac-solasodine, which can potentially serve as a platform for the selective functionalization of C(3)–OH and N–H of solasodine. The simple operations without purification by column chromatography make this method suitable to scale up.