N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable,Selective Melatonin Receptor Ligands

The class of N‐(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT₂‐selective partial agonist UCM765 (N‐{2‐[(3‐methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses ≥40 mg kg^?1 (s.c.), in spite of its sub‐nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC–MS, synthesized, and in vitro tested for their affinity toward MT₁ and MT₂ receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N‐{2‐[(3‐bromophenyl)‐(4‐fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT₂‐selective partial agonist) and a significantly longer half‐life in the presence of rat liver S9 fraction.     

Melatonin Signaling Pathways Implicated in Metabolic Processes in Human Granulosa Cells (KGN)

Female reproduction depends on the metabolic status, especially during the period of folliculogenesis. Even though it is believed that melatonin can improve oocyte competence, there is still limited knowledge of how it can modulate metabolic processes during folliculogenesis and which signaling pathways are involved in regulating gene expression. To investigate the effects of melatonin on metabolic signals during the antral stage of follicular development, human granulosa-like tumor cells (KGN) were treated with melatonin or forskolin, and gene expression was analyzed with RNA-seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, p ≤ 0.05), 1009 and 922 genes were identified as differentially expressed in response to melatonin and forskolin, respectively. Analysis of major upstream regulators suggested that melatonin may activate PKB/mTOR signaling pathways to program the metabolism of KGN cells to support slower growth and differentiation and to prevent follicular atresia. Similarly, PKA activation through stimulation of cAMP synthesis with FSK seemed to exert the same effects as melatonin in reducing follicular growth and regulating differentiation. This study suggests that melatonin may act through PKA and PKB simultaneously in human granulosa cells to prevent follicular atresia and early luteinization at the antral stage.     

Water soluble imide—amide copolymers: Iv. Flocculation and surface active properties of poly(acrylamide-co-sodium N-(4-sulfophenyl)maleimide)

Six new poly(acrylamide-co-sodium N-(4-sulfophenyl)maleimide) (PAMSM) water-soluble copolymers have been prepared with several levels of imide ring incorporation into the backbone of the polymer chain to test the effectiveness of increased chain stiffness on the efficiency of fiocculation. Sufficient material was obtained from the synthetic experiments to enable the surface active properties of three of these copolymers to be tested. PAMSM copolymers containing 7, 15, and 25 mol % imide performed poorly compared to commercial partially hydrolyzed polyacrylamides (HPAM) when used to flocculate an aqueous 3% calcium-montmorillonite suspension at pH 4·0 and pH 7·5. This was probably because of a major difference between the dissociation constants of the anionic functionalities of the new vs existing commercial polymer flocculants, complicated by the possibility that the molecular weights of the new copolymers were too low. The three PAMSM copolymers behaved as dispersants instead of flocculants when tested on a 3% kaolinite suspension in water at pH 4·5. Their effectiveness as dispersants increased with increasing imide content. PAMSM-1a (7% imide), PAMSM-3 (25% imide) and polystyrene sulfonate (500 000 mol. wt) all acted as weak dispersants when tested on a 3% hematite suspension in water at pH 4·5, 6–0, and 8·7.     

Synthesis and Biological Evaluation of 10-Substituted Camptothecin Derivatives with Improved Water Solubility and Activity

Despite remarkable clinical achievements, camptothecin (CPT) still suffers from poor solubility and severe toxicity. Therefore, it is necessary to redevelop CPT derivatives as supplementary antitumor agents with good water solubility and small side effects. In this work, 27 camptothecin derivatives were synthesized and screened for their cytotoxicity against A549 (lung) and HCT-116 (colon) cancer cell lines. Among them, compound B7 , 7-ethyl-10-(2-oxo-2-(4-methylpiperidin-1-yl)ethoxy)camptothecin,was demonstrated in vitro to be a more potent antitumor agent than SN-38 by comparison of their inhibitory activities against cell proliferation and colony formation and interference effect on process of cell cycle and cell apoptosis. Additionally, a molecular docking model revealed that B7 can interact with the topoisomerase I–DNA complex, and that the solubility of B7 reached 5.73 μg/mL in water. Moreover, B7 significantly inhibited tumor growth in an A549 xenograft model at dosages of 0.4 and 2.0 mg/kg, and exhibited minimum lethal doses comparable to those of irinotecan. These results indicated that B7 , with improved solubility, enhanced activity and acceptable acute toxicity, can be used as a lead compound for the development of novel anticancer agents.     

Towards the development of mixed MT(1)-agonist/MT(2)-antagonist melatonin receptor ligands

Herein we report attempts to optimize the pharmacological properties of 5-(2-hydroxyethoxy)-N-acetyltryptamine (5-HEAT), a melatonin receptor ligand previously described by us. Several 5-substituted and 2,5-disubstituted N-acyltryptamines were synthesized and evaluated in vitro for the human cloned MT(1) and MT(2) receptors. From this series of N-acyltryptamines the 2-bromo derivative (5 c) retains the interesting efficacy profile of 5-HEAT and shows increased melatonin receptor affinities; it represents one of the first examples of a high-affinity MT(1) agonist/MT(2) antagonist. Some other full agonists for both melatonin receptors which exhibit similar or increased affinity relative to that of melatonin were obtained.     

An Enhanced Water Solubility and Stability of Anthocyanins in Mulberry Processed with Hot Melt Extrusion

Mulberry fruits are rich sources of anthocyanins that exhibit beneficial biological activity. These anthocyanins become instable in an aqueous media, leading to their low bioavailability. In this study, a colloidal dispersion was produced by processing mulberry samples with hot-melt extrusion. In this process, hydrophilic polymer matrices were used to disperse the compound in an aqueous media. Mulberry samples were processed with hot-melt extrusion and in the presence of an ionization agent and sodium alginate to form mulberry-extrudate solid formulations. The particle size of mulberry-extrudate solid formulations decreased, while the total phenol content, the total anthocyanin content, and solubility increased. Fourier transform infrared spectroscopy (FT-IR) revealed that mulberry-extrudate solid formulations now contained new functional groups, such as –COOH group. We investigated whether mulberry-extrudate solid formulations had a positive impact on the stability of anthocyanins. The non-extrudate mulberry sample and mulberry-extrudate solid formulations were incubated with a simulated gastric fluid system and an intestinal fluid system. The number of released anthocyanins was determined with HPLC. We found that anthocyanins were released rapidly from non-extrudate mulberry extract. Mulberry-extrudate solid formulations contained a large number of available anthocyanins even after being incubated for 180 min in the intestinal fluid system. Thus, hot-melt extrusion enhanced water solubility and stability of anthocyanins with the prolonged release.     

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor,O-GlcNAcylation,Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.     

Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) in Innate Immunity. TLRs,NLRs, and RLRs Ligands as Immunotherapeutic Agents for Hematopoietic Diseases

The innate immune system plays a pivotal role in the first line of host defense against infections and is equipped with patterns recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRRS, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) recognize distinct microbial components and directly activate immune cells. TLRs are transmembrane receptors, while NLRs and RLRs are intracellular molecules. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. The innate immune system also influences pathways involved in cancer immunosurveillance. Natural and synthetic agonists of TLRs, NLRs, or RLRs can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment, and are being explored as promising adjuvants in cancer immunotherapies. In this review, we provide a concise overview of TLRs, NLRs, and RLRs: their structure, functions, signaling pathways, and regulation. We also describe various ligands for these receptors and their possible application in treatment of hematopoietic diseases.     

Pramipexole Derivatives as Potent and Selective Dopamine D3 Receptor Agonists with Improved Human Microsomal Stability

Herein we report the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective agonists of the dopamine‐3 (D₃) receptor. A number of these new compounds bind to the D₃ receptor with sub‐nanomolar affinity and show excellent selectivity (>10 000) for the D₃ receptor over the D₁ and D₂ receptors. For example, compound 23 (N‐(cis‐3‐(2‐(((S)‐2‐amino‐4,5,6,7‐tetrahydrobenzo[d]thiazol‐6‐yl)(propyl)amino)ethyl)‐3‐hydroxycyclobutyl)‐3‐(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)benzamide) binds to the D₃ receptor with a K_i value of 0.53 nM and shows a selectivity of >20 000 over the D₂ and D₁ receptors in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes. Moreover, in vitro functional assays showed it to be a full agonist for the human D₃ receptor.     

Ru(III) Complexes with Lonidamine-Modified Ligands

A series of bifunctional Ru(III) complexes with lonidamine-modified ligands (lonidamine is a selective inhibitor of aerobic glycolysis in cancer cells) was described. Redox properties of Ru(III) complexes were characterized by cyclic voltammetry. An easy reduction suggested a perspective for these agents as their whole mechanism of action seems to be based on activation by metal atom reduction. New compounds demonstrated a more pronounced antiproliferative potency than the parental drug; individual new agents were more cytotoxic than cisplatin. Stability studies showed an increase in the stability of complexes along with the linker length. A similar trend was noted for antiproliferative activity, cellular uptake, apoptosis induction, and thioredoxin reductase inhibition. Finally, at concentrations that did not alter water solubility, the selected new complex evoked no acute toxicity in Balb/c mice.     

Poly(amide imide)s and poly(amide imide) composite membranes by interfacial polymerization

Novel amic acid diamines (AADs) (2‐carboxyterephthalamido‐bis(alkyl or aryl amine)s, H₂N? X? NH(O?)C? C₆H₃(COOH)? C(?O)NH? X? NH₂, where X is were synthesized by reacting trimellitic anhydride chloride with aromatic or aliphatic diamines in dimethylformamide at 5–10 °C. Poly(amide imide)s (PAIs) with an amide to imide ratio of three in the polymer chains were prepared by interfacial polycondensation of the AADs in aqueous alkaline solution with isophthaloyl chloride or terephthaloyl chloride in dichloromethane at ambient temperature to form poly(amide amic acid)s, followed by their subsequent thermal cycloimidization. All of the PAIs were soluble in polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N‐methylpyrrolidone, and have inherent viscosities in the range 0.15–0.48 dL g^?1. The polymers were characterized by IR and NMR spectroscopy, TGA and DSC techniques. The PAIs have initial decomposition temperatures in the range 250–460 °C in air, and glass transition temperatures of 128–320 °C, depending upon the structures of the monomers. Composite membranes containing a poly(amide amic acid) and poly(amide imide) barrier layer on the top of a porous polyethersulfone support were prepared by in situ interfacial polymerization of the AADs in aqueous alkaline solution with trimesoyl chloride in hexane, and subsequent curing. The performances of these membranes were evaluated by using aqueous feed solutions containing 2000 ppm NaCl, Na₂SO₄ or CaCl₂. Copyright © 2006 Society of Chemical Industry     

Synthesis and characterization of poly(ester amide)s containing crystallizable amide segments

High molecular weight segmented poly(ester amide)s were prepared by melt polycondensation of 1,4-butanediol, dimethyl adipate and a preformed bisamide-diol based on 1,4-diaminobutane and ε-caprolactone. By varying the ratio of the bisamide-diol and 1,4-butanediol, a series of polymers was obtained with a hard segment content between 10 and 85 mol%. FT-IR and WAXD analysis revealed that the poly(ester amide)s crystallize in an α-type phase similar to the α-phase of even-even nylons. These polymers all have a micro-phase separated structure with an amide-rich hard phase and an ester-rich flexible soft phase. The polymers have a low and a high melt transition, corresponding with the melting of crystals comprising single ester amide sequences and two or more ester amide sequences, respectively. The low melt transition is between 58 and 70 °C and is independent of polymer composition. By increasing the hard segment content from 10 to 85 mol% the high melt transition increased from 83 to 140 °C while the glass transition temperature increased from −45 to −5 °C. Likewise, the elastic modulus increased from 70 to 524 MPa, the stress at break increased from 8 to 28 MPa while the strain at break decreased from 820 to 370%. Thermal and mechanical properties can thus be tuned for specific applications by varying the hard segment content in these segmented polymers.     

Pt(IV) Prodrugs with NSAIDs as Axial Ligands

A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure–activity ratio, and therapeutic efficacy.     

N-(p-Bromophenyl)maleimide and its copolymers with alkyl methacrylates

Copolymers of methyl, ethyl, butyl, pentyl, or octyl methacrylate with N-(p-bromophenyl)maleimide were synthesized by free-radical bulk polymerization using benzoyl peroxide as initiator. N-(p-bromophenyl)maleimide was prepared from maleic anhydride and p-bromoaniline in a two-step reaction. Thermal stability, chemical resistance, hardness, and Vicat softening point of the copolymers have been measured. The influence of N-(p-bromophenyl)maleimide content in the copolymers and the length of alkyl groups in methacrylates on their properties is discussed.     

Novel diols containing ester and amide groups and resulting poly(ester amide ester)s

The reaction of terephthaloyl chloride and 4‐hydroxybenzoic acid resulted in terephthalyl bis(4‐oxybenzoic) acid. This diester diacid was converted into its corresponding diester diacid chloride (terephthaloyl dioxydibenzoylchloride) via a reaction with thionyl chloride. Diols with preformed ester and amide groups were prepared through the reaction of terephthaloyl dioxydibenzoylchloride with 4‐aminophenol and 5‐amino‐1‐naphthol. Polycondensation reactions of the prepared diols with different aromatic and aliphatic diacid chlorides afforded eight aromatic and semiaromatic poly(ester amide ester)s. The polymers were fully characterized, and their physical and thermal properties were studied. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 2699–2703, 2004     

Copolymerization of methyl methacrylate with N-(methoxyphenyl) itaconimides

This article describes the synthesis and characterization of N-(3-methoxyphenyl) itaconimide (MAI) and N-(4-methoxyphenyl) itaconimide (PAI) obtained by the reaction of itaconic anhydride with m-anisidine and p-anisidine, respectively. Structural and thermal characterization of MAI and PAI monomers was performed with Fourier transform infrared (FTIR), ¹H-NMR, differential scanning calorimetry (DSC), and thermogravimetric analysis. Copolymerization of methyl methacrylate (MMA) with various amounts of MAI or PAI ranging from 0.1 to 0.5 was performed in solution with azobisisobutyronitrile as an initiator. Structural and molecular characterization of copolymers was performed with FTIR, ¹H-NMR, elemental analysis, and gel permeation chromatography. The nitrogen percentage was used to calculate the copolymer composition. The monomer reactivity ratios for MMA–MAI copolymers were found to be 1.00 ± 0.01 for MMA and 0.99 ± 0.07 for MAI; those for MMA–PAI copolymers were 0.93 ± 0.02 for MMA and 1.11 ± 0.10 for PAI. The molecular weights of the copolymers were in the range of 0.94–9.7 × 10³ (number-average molecular weight) and 3.3–101.8 × 10³ (weight-average molecular weight), with polydispersity indices in the range of 1.5–4.1. The molecular weight decreased with the increasing molar fraction of imide in the polymer backbone. The glass-transition temperature, as determined from DSC scans, increased with increasing amounts of itaconimides in the copolymers. A significant improvement in the char yield, as determined by thermogravimetry, was observed upon copolymerization. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Amine functionalization of poly(styryl)lithium with N-(benzylidene)trimethylsilylamine

Functionalization reactions of poly(styryl)lithium with N-(benzylidene)-trimethylsilylamine produce polymers containing significant amounts of coupling products for M_n = 2.8 × 10³g/mol (19% coupling) and M_n = 15 × 10³g/mol (15% coupling). Isolation and characterization of the products for the amination of poly(styryl)lithium with M_n = 2.8 × 1³g/mol indicates that the non-coupled products consist of a primary amine-terminated polymer (69% yield) and an acetophenone-type functionalized polymer (12% yield). The dimeric product (19% yield) has a primary amine functional group. The formation of these products is rationalized by a Cannizzaro-type reaction of the initially formed polymeric lithium silylamide product with excess N-(benzylidene)(trimethylsilylamine to form the corresponding polymer with imine chain-end functionality which can react with another molecule of poly(styryl)lithium to form dimer product or hydrolyze to the acetophenone functionality on work-up.     

NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation

Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.