Chune Dong

Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer

A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In this article, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These OBHS-HDACi conjugates exhibited good ER binding affinity and excellent ERα antagonistic activity, and they also exhibited potent inhibitory activities against HDACs. Compared with the approved drug tamoxifen, these conjugates exhibited higher antitumor potency in ERα-positive breast cancer cells (MCF-7). Moreover, these conjugates not only showed selective anticancer activity that was more potent against MCF-7 cells than DU 145 (prostate cancer), but they had no toxicity toward normal cells.

Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands.

Previously, we discovered estrogen receptor (ER) ligands with a novel three‐dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 oxabicycloheptene sulfonates, varying the phenyl sulfonate group. As with the parent compound, 5,6‐bis‐(4‐hydroxyphenyl)‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2‐sulfonic acid phenyl ester (OBHS), these compounds showed preferential affinity for ERα, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERα. A few analogues exhibit ERα binding affinities that are comparable to or, in the case of the ortho‐chloro analogue, higher than that of OBHS itself. In cell‐based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism.

Fabrication and superconductivity of Na x Ta S 2 crystals

In this paper we report the growth and superconductivity of NaxTaS2 crystals. The structural data deduced from x-ray diffraction pattern shows that the sample has the same structure as 2H-TaS2. A series of crystals with different superconducting transition temperatures (T-c) ranging from 2.5 K to 4.4 K were obtained. It is found that the T-c rises with the increase of Na content determined by energy-dispersive x-ray microanalysis(EDX) of scanning electron microscope (SEM) on these crystals. Compared with the resistivity curve of un-intercalated sample 2H-TaS2 (T-c=0.8 K, T(CDW)approximate to 70 K), no signal of charge density wave (CDW) was observed in samples Na0.1TaS2 and Na0.05TaS2. However, in some samples with lower T-c, the CDW appears again at about 65 K. Comparison between the anisotropic resistivity indicates that the anisotropy becomes smaller in samples with more Na intercalation (albeit a weak semiconducting behavior along c-axis) and thus higher T-c. It is thus concluded that there is a competition between the superconductivity and the CDW. With the increase of sodium content, the rise of T-c in NaxTaS2 is caused mainly by the suppression to the CDW in 2H-TaS2, and the conventional rigid band model for layered dichalcogenide may be inadequate to explain the changes induced by the slight intercalation of sodium in 2H-TaS2.

Superconducting properties and c-axis superstructure of Mg1xAlxB2

The superconducting and structural properties of a series of Mg1-xAlxB2 samples have been investigated. X-ray diffraction results confirmed the existence of a structural transition associated with a significant change in interboron layer distance as reported previously by Slusky Moreover, transmission-electron-microscopy observations revealed the existence of a superstructure with doubled lattice constant along the c-axis direction. We propose that this superstructure is probably related to the structural transition. The modifications of the superconducting transition temperature T-c, the normal-state resistivity, and the upper critical field B-c2(0) by Al doping are discussed in terms of Al-substitution-induced changes in the electronic structure at the Fermi energy.

Identification and Structure-Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide

To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ERα selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERα-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.

An expedient approach to highly enantioenriched cyclic nitrones mediated by robust and recoverable C3-symmetric cinchonine-squaramide catalysts

The C3-symmetric cinchonine-squaramide catalyzed asymmetric Michael addition of β-ketosulfones to nitroalkenes is presented. Subsequent transformation leads to chiral cyclic nitrones with excellent results (up to 85% yield and >99% ee). The catalyst can be recovered and reused for six cycles without losing activity and selectivity.

Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds.

This review seeks to provide coverage on the recent advances in chiral squaramide-catalyzed asymmetric transformations and their applications in the synthesis of a variety of chiral biologically active compounds. It aims to give an overview highlighting the new reaction types and enantioenriched medicinal scaffolds developed in the last few years.

Facile synthesis of 1,3,4-benzotriazepines and 1-arylamide-1H-indazoles via palladium-catalyzed cyclization of aryl isocyanates and aryl hydrazones under microwave irradiation

A strategy involving palladium-catalyzed cyclization of halo-phenyl hydrazones and aryl isocyanates provides a convenient approach to the synthesis of 1,3,4-benzotriazepines (4) or 1-arylamide-1H-indazoles (5) in good isolated yields. Microwave irradiation was found to afford high reaction efficiency, while the choice of halophenyl hydrazone had an effect on the pathway of the reaction.

Rapid preparation of MgB2 superconductor using hybrid microwave synthesis

A novel hybrid microwave procedure for the synthesis of MgB2 superconductor was demonstrated. This procedure has advantages over other methods using sealed tubes or high pressure. Using silicon carbide (SiC) powder as the susceptor, the MgB2 samples can be synthesized in about 10 min by microwave heating. The superconducting transition width of the MgB2 sample was less than 0.3 K, and its zero-resistance temperature was 39.5 K. The critical current density Jc estimated from the magnetization hysteresis is 4.5 × 104 A cm−2 at 20 K and 1 T, which is close to that of the samples prepared by high-pressure sintering.

Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure–activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides

Compounds that block estrogen action through the estrogen receptor (ER) or downregulate ER levels are useful for the treatment of breast cancer and endocrine disorders. In our search for structurally novel estrogens having three-dimensional core scaffolds, we found some compounds with a 7-oxabicyclo[2.2.1]heptene core that bound well to the ERs. The best of these compounds, a phenyl sulfonate ester (termed OBHS for oxabicycloheptene sulfonate), was a partial antagonist on both ERα and ERβ. Although OBHS bears no structural resemblance to other estrogen antagonists, it appears to achieve its partial antagonist character by stabilizing a novel conformation of the ER that involves a significant distortion of helix-11. To enhance the antagonist properties of these oxabicyclo[2.2.1]heptane core ligands, we expanded the functional diversity of OBHS by replacing the sulfonate with secondary or tertiary sulfonamides (-SO(2)NR-), isoelectronic and potentially isostructural molecular replacements. An array of 16 OBHS sulfonamide analogues were prepared through a Diels-Alder reaction of a 3,4-diarylfuran using various N-aryl vinyl sulfonamide dienophiles. While the more polar secondary sulphonamides were weak ligands, certain of the tertiary sulfonamides had very good ER binding affinity. In HepG2 cell reporter gene assays, the sulphonamides had moderate potency, but they showed lower intrinsic transcriptional activity on ERα than the selective estrogen receptor modulator (SERM) hydroxytamoxifen or OBHS, and they were inverse agonists on ERβ. Thus, the behaviour of these OBH-sulfonamides more closely mirrors the activity of full antagonists like the drug fulvestrant (ICI 182 780), and their greater antagonist biocharacter appears to arise from an accentuated distortion of helix-11.