Binding to DPF-motif by the POB1 EH domain is responsible for POB1-Eps15 interaction

Background  

Eps15 homology (EH) domains are protein interaction modules binding to peptides containing Asn-Pro-Phe (NPF) motifs and mediating critical events during endocytosis and signal transduction. The EH domain of POB1 associates with Eps15, a protein characterized by a striking string of DPF triplets, 15 in human and 13 in mouse Eps15, at the C-terminus and lacking the typical EH-binding NPF motif.     

Synthesis and anticancer activity of some 1,5-diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines

Abstract  

The deregulation of cell cycle components in cancer cells has provided a rationale for the development of small molecule inhibitors of cyclin-dependent kinases as novel anticancer drugs. A series of 1,5-diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines was synthesized and their kinase inhibitory activity and cytotoxicity against several cancer cell lines has been evaluated. Some of the compounds of the series exhibited induction of caspase-dependent cell death and inhibition of cyclin-dependent kinase 2 (CDK2).     

Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II

Background  

Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II.     

Mn-doped ZnSe d-dots-based α-methylacyl-CoA racemase probe for human prostate cancer cell imaging

In this paper, we report the successful use of non-cadmium-based Mn-doped ZnSe d-dots (Mn/ZnSe) as highly efficient and nontoxic optical probes for human prostate cancer cells imaging. Mn/ZnSe d-dots are directly prepared in aqueous solution. The α-methylacyl-CoA racemase (AMACR) is overexpressed in prostate cancers; the presence of antibodies specific for AMACR is more sensitive and specific than serum prostate specific antigen levels in distinguishing patients with prostate cancers. Mn/ZnSe d-dots were linked to anti-AMACR to form Mn/ZnSe d-dots-anti-AMACR bioconjugates for the direct prostate cancer cell imaging. 3-(4,5-Dimethylthiazol-2-yl)-2 and 5-diphenyl tetrazolium bromide assay demonstrated that Mn/ZnSe d-dots exhibited favorable cytocompatibility to LNCaP cells with high concentration (1 mM) and long-time incubation (24 h). Furthermore, cellular imaging results demonstrated that Mn/ZnSe d-dots were remarkably efficacious for high-specificity cell imaging. The antibody-mediated delivery of the bioconjugates was further confirmed by the observation of no fluorescence signals in vitro targeting in nonprostate-cancer-based cell lines which are negative for AMACR. Mn/ZnSe d-dots as non-cadmium-based safe and efficient optical imaging nanoprobes could therefore be used for targeting imaging and treatment of cancers in the early stage.     

Synthesis and biological activity of novel 4- and 6-(1-alkyl/aryl-1H-benzimidazol-2-yl)benzene-1,3-diols

Abstract  

A one-pot synthesis of new biologically active 4- and 6-(1-alkyl/aryl-1H-benzimidazol-2-yl)benzene-1,3-diols has been developed. The compounds were obtained by the reaction of aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione] with N-substituted benzene-1,2-diamines. Elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data were used to elucidate their structures. The developed method offers short reaction times, easy and quick isolation of the products, and good yields. The antiproliferative properties of the synthesized compounds were investigated against a panel of human cancer cell lines. Some of the tested compounds showed significant cytotoxic activity.     

Synthesis of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitriles: in vitro anticancer activity against MCF-7, PC-3 and A2780 cancer cell lines

A series of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitrile (2–9) were designed and synthesized to develop new cancer drugs. The structures of synthesized compounds 2–9 were described by using melting point, mass (MALDI-TOF-MS), FT-IR, elemental analysis, ¹H, ¹³C, ¹³C-APT and 2D NMR spectroscopy. The in vitro anticancer activities of 2–9 against human breast cancer (MCF-7), human prostate cancer (PC-3) and human ovarian cancer cells (A2780) were investigated by [3-(4,5-dimethylthiazol)-2-yl]-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assay method. Additionally, the LogIC₅₀ values of these compounds on A2780, MCF-7 and PC-3 cell lines were calculated by using inhibition % values by the GraphPad Prism 6 program on a computer. The results indicated that these compounds have high anticancer activity against MCF-7, PC-3 and A2780 cell lines (especially A2780 cell lines, p < 0.05).     

Cooperative stabilisation of 14-3-3σ protein–protein interactions via covalent protein modification

14-3-3 proteins are an important family of hub proteins that play important roles in many cellular processes via a large network of interactions with partner proteins. Many of these protein–protein interactions (PPI) are implicated in human diseases such as cancer and neurodegeneration. The stabilisation of selected 14-3-3 PPIs using drug-like ‘molecular glues’ is a novel therapeutic strategy with high potential. However, the examples reported to date have a number of drawbacks in terms of selectivity and potency. Here, we report that WR-1065, the active species of the approved drug amifostine, covalently modifies 14-3-3σ at an isoform-unique cysteine residue, Cys38. This modification leads to isoform-specific stabilisation of two 14-3-3σ PPIs in a manner that is cooperative with a well characterised molecular glue, fusicoccin A. Our findings reveal a novel stabilisation mechanism for 14-3-3σ, an isoform with particular involvement in cancer pathways. This mechanism can be exploited to harness the enhanced potency conveyed by covalent drug molecules and dual ligand cooperativity. This is demonstrated in two cancer cell lines whereby the cooperative behaviour of fusicoccin A and WR-1065 leads to enhanced efficacy for inducing cell death and attenuating cell growth.

The aminothiol WR-1065 covalently modifies 14-3-3σ to stabilse its interactions with p53 and ERα. It enhances the effect of fusicoccin A via a cooperative mechanism that leads to 14-3-3 partner-protein specific activty against cancer cells.      

First Asymmetric Total Synthesis of (R,E)-1-[4-(3-Hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-diol

A new anti-inflammatory active phenylpropenoid, (R,E)-1-[4-(3-hydroxyprop-1-enyl) phenoxyl]-3-methylbutane-2,3-diol (1), isolated from the stem wood of Zanthoxylum integrifoliolum, has been synthesized for the first time using commercially available 4-hydroxy benzaldehyde (2). The key step involves the Sharpless asymmetric dihydroxylation of olefin (3).

Efficient,Stereoselective Approach to the Synthesis of 3-(1-Phenyl-2-(Z-styrylsulfonyl)-1H-imidazol-4-yl)-2H-chromen-2-ones

Reaction of phenyl acetylene with 3-(1-aryl-2-mercapto-4-imidazolyl)-2H-1-benzopyran-2-ones (4) in the presence of sodium hydroxide in absolute ethanol led to the formation of 3-(1-phenyl-2-(Z-styrylthio)-1H-imidazol-4-yl)-2H-chromen-2-ones (6) in excellent yields. These, on further oxidation with H₂O₂/AcOH, gave the corresponding sulfones (7) with retention of stereochemistry.

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Abstract  

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles, except for nitro derivatives, where both (Z)- and (E)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations is discussed and the stereochemistries of all products were established by NMR experiments.     

A novel synthetic approach towards pyrazole-4-carboxamides using N-(3-(dimethylamino)-2-formylacryloyl)formamide

Abstract  

A novel synthesis of pyrazole-4-carboxamides is reported. The reaction of N-(3-(dimethylamino)-2-formylacryloyl)formamide, an intermediate obtained by Vilsmeier–Haack formylation of acetonitrile, with hydrazine hydrate or monosubstituted hydrazines provides such compounds in good yields. This method has advantages over other methods for construction of such ring systems previously described in the literature.     

Study on poly(oxybenzoate-p-trimethylene terephthalate) copolymer

This study examined copolymers synthesized from poly(trimethylene terephthalate) (PTT) and p-acetoxybenzoic acid using solution proton nuclear magnetic resonance (NMR) spectroscopy. Proton NMR spectra showed that these p-oxybenzoate (POB)/PTT copolyesters were almost random copolymers because the preference factor of POB bonded to another POB unit in these copolyesters is close to 1.0 with a POB content between 20 and 80 mol%.The melting and crystallization behaviors of these copolyesters were studied by differential scanning calorimetry (DSC). In the heating DSC scan of the POB rich composition, the endothermic peak is weaker because the enthalpy of fusion decreased due to a melting transition from a crystalline to anisotropy liquid state. Thermogravimetric analysis results indicated that the decomposition temperature (T_d) increased with POB content. The crystalline morphology of the copolyester was further investigated with a polarized optical microscope, indicating that the POB/PTT copolyesters with 60 mol% POB are highly anisotropic in the liquid state.     

EAAC1 is expressed in rat and human prostate epithelial cells; functions as a high-affinity L-aspartate transporter; and is regulated by prolactin and testosterone

Background  

Prostate epithelial cells accumulate a high level of aspartate that is utilized as a substrate for their unique function of production and secretion of enormously high levels of citrate. In most mammalian cells aspartate is synthesized; and, therefore is a non-essential amino acid. In contrast, in citrate-producing prostate cells, aspartate is an essential amino acid that must be derived from circulation. The prostate intracellular/extracellular conditions present a 40:1 concentration gradient. Therefore, these cells must possess a plasma membrane-associated aspartate uptake transport process to achieve their functional activity. In earlier kinetic studies we identified the existence of a unique Na+-dependent high-affinity L-aspartate transport process in rat prostate secretory epithelial cells. The present report is concerned with the identification of this putative L-aspartate transporter in rat and human prostate cells.     

Synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones under microwave irradiation

Abstract  A facile procedure for the synthesis of quinoxalines is being reported starting from 3-(2-bromoacetyl)coumarins or 3-(2-bromobutanoyl)coumarins and substituted o-phenylenediamines. The reactions were carried out under catalyst-free and microwave irradiation conditions producing the title compounds in moderate to excellent yields in a short time with easy workup. The structures of all new compounds have been confirmed on the basis of their IR, ¹H NMR, ¹³C NMR, and HRMS data. Graphical Abstract        

Poly(β‐cyclodextrin)/Curcumin Self‐Assembly: A Novel Approach to Improve Curcumin Delivery and its Therapeutic Efficacy in Prostate Cancer Cells

A novel PCD/CUR self‐assembly approach for improved curcumin delivery to prostate cancer cells is described. The formation of PCD/CUR was confirmed using FTIR, DSC, TGA, and SEM/TEM, and their stability and solubility under physiological conditions was demonstrated. A mechanism for self‐assembly is proposed. Intracellular uptake of the self‐assemblies was studied by flow cytometry and immunofluorescence microscopy. The therapeutic efficacy was determined by cell proliferation and colony formation assays using C4‐2, DU145 and PC3 prostate cancer cells. The results suggest that the PCD/CUR formulation could be a useful system for improving curcumin delivery and its therapeutic efficacy in prostate cancer.

     

Synthesis and Anticancer Activity Evaluation of 5-[2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-thiazolidinones

A series of novel 5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum–thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (2h) with the highest level of antimitotic activity with mean GI₅₀/TGI values of 1.57/13.3 μM and a certain sensitivity profile against leukemia (MOLT-4, SR), colon cancer (SW-620), CNS cancer (SF-539), melanoma (SK-MEL-5), gastric cancer (AGS), human colon cancer (DLD-1), and breast cancers (MCF-7 and MDA-MB-231) cell lines. The hit compounds 2f, 2i, 2j, and 2h have been found to have low toxicity toward normal human blood lymphocytes and a fairly wide therapeutic range. The significant role of the 2-chloro-3-(4-nitrophenyl)prop-2-enylidene (Ciminalum) substituent in the 5 position and the substituent’s nature in the position 3 of core heterocycle in the anticancer cytotoxicity levels of 4-thiazolidinone derivatives have been established     

A Ti3C2TX/Pt–Pd based amperometric biosensor for sensitive cancer biomarker detection

The detection of cancer biomarkers is of great significance for the early screening of cancer. Detecting the content of sarcosine in blood or urine has been considered to provide a basis for the diagnosis of prostate cancer. However, it still lacks simple, high-precision and wide-ranging sarcosine detection methods. In this work, a Ti₃C₂T_X/Pt–Pd nanocomposite with high stability and excellent electrochemical performance has been synthesized by a facile one-step alcohol reduction and then used on a glassy carbon electrode (GCE) with sarcosine oxidase (SO_x) to form a sarcosine biosensor (GCE/Ti₃C₂T_X/Pt–Pd/SO_x). The prominent electrocatalytic activity and biocompatibility of Ti₃C₂T_X/Pt–Pd enable the SO_x to be highly active and sensitive to sarcosine. Under the optimized conditions, the prepared biosensor has a wide linear detection range to sarcosine from 1 to 1000 µM with a low limit of detection of 0.16 µM (S/N = 3) and a sensitivity of 84.1 µA/mM cm². Besides, the reliable response in serum samples shows its potential in the early diagnosis of prostate cancer. More importantly, the successful construction and application of the amperometric biosensor based on Ti₃C₂T_X/Pt–Pd will provide a meaningful reference for detecting other cancer biomarkers.     

Synthesis of 1-(2-furyl)-2-nitropropen-3-ones

1-(2-Furyl)-2-nitropropen-3-ones were synthesized by reaction of nitrogen tetroxide with a number of , -unsaturated furylcarbonyl compounds. The 5-nitrofuryl derivative was obtained from 1-(2-furyl)-3-(4-methoxyphenyl)propen-3-one when the excess amount of N₂O₄ was increased. Replacement of bromine by a nitro group in the furan ring is observed in the case of the 5-bromofuryl derivative.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1604–1606, December, 1977.     

The crystal structures ofbis-{(2-benzotrifluoride)-[(2-oxo-3H-naphth-3-ylidene)-methyl]-aminato} Copper(II) andbis-{(3-benzotrifluoride)-[(2-oxo-3H-naphth-3-ylidene)-methyl]-aminato} Copper(II)

Summary TheSchiff base ligands 3-[(2-benzotrifluoride)-2-hydroxy-3H-naphth-3-ylidene)-methyl] aldamine (1) and 3-[(3-benzotrifluoride)-2-hydroxy-3H-naphth-3-ylidene)-methyl] aldamine (2) and their corresponding Cu(II) complexes (I, II) were synthesized. The crystal structures ofbis-{(2-benzotrifluoride)-[(2-oxo-3H-naphth-3-ylidene)]-methyl]-aminato} Copper(II) (I) andbis-{(3-benzotrifluoride)-[(2-oxo-3H-naphth-3-ylidene)-methyl]-aminato} Copper(II) (II) were determined. CompoundI crystallizes in the triclinic crystal system (a=12.561(3),b=16.211(4),c=8.007(2) Å, =96.29(2), =101.42(2), =97.10(2)°, space group ,Z=2); compoundII crystallizes in the monoclinic crystal system (a=5.064(2),b=19.172(4),c=15.111(3) Å, =95.05(2)°, space group P2₁/c,Z=2). The X-ray diffraction study shows that the geometry around the metal atom is square planar for both copper complexes.

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Kristallstruktur vonbis-{(2-Benzotrifluorid)-[(2-oxo-3H-naphth-3-yliden)-methyl]-aminato}-Kupfer(II) undbis-{(3-Benzotrifluorid)-[(2-oxo-3H-naphth-3-yliden)-methyl]-aminato}-Kupfer(II)

Zusammenfassung DieSchiffschen Basen 3-[(2-Benzotrifluorid)-2-hydroxy-3H-naphth-3-yliden)-methyl]-aldamin (1) und 3-[(3-Benzotrifluorid)-2-hydroxy-3H-naphth-3-yliden)-methyl]-aldamin (2) sowie ihre entsprechenden Cu(II)-Komplexe (I,II) wurden synthetisiert und ihre Struktur im Kristall bestimmt. VerbindungI kristallisiert triklin (a=15.561(3),b=16.211(4),c=8.007(2) Å, =96.29(2), =101.42(2), =97.10(2)°, Raumgruppe ,Z=2); VerbindungII kristallisiert monoklin (a=5.064(2),b=19.172(4),c=15.111(3) Å, =95.05(2)°, Raumgruppe P2₁/c,Z=2). Aus der Röntgenstrukturanalyse ergibt sich eine quadratisch planare Geometrie der Komplexe.