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Abstract: Steric and electronic parameters, such as the anomeric effect (AE) and gauche effect play significant roles in steering the North⇆South equilibrium of nucleosides in solution. Two isomeric oxa-bicyclo[3.1.0]hexane nucleosides that are conformationally locked in either the North or the South conformation of the pseudorotational cycle were designed to study the consequences of having the AE operational or not, independent of other parameters. The rigidity of the system allowed the orientation of the orbitals involved to be set in ‘fixed’ relationships, either antiperiplanar where the AE is permanently ‘on’, or gauche where the AE is impaired. The consequences of these two alternatives were subjected to high-level calculations and measured experimentally by X-ray crystallography, hydrolytic stability of the glycosyl bond, and pK a values. [ABSTRACT FROM AUTHOR]

Abstract: Novel iso-d-2′,3′-dideoxythianucleoside derivatives 1–4 were designed and asymmetrically synthesized as a bioisostere of lamivudine to search for new anti-HIV agents. The information about using sulfur participation occurred on DAST fluorination and Mitsunobu reaction will be of great help in synthesizing sulfur-containing compounds. Final compounds 1–4 were evaluated against HIV-1 and 2, HSV-1 and 2, EMCV, Cox. B3, VSV, FluA (Taiwan), FluA (Johan.), FCV, and FIP. Only cytosine analogue 3 showed a potent anti-VSV activity (EC50 =9.43μg/mL). This result implies that iso-2′,3′-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent. [Copyright &y& Elsevier]

Halogenated analogues of neplanocin A were synthesized from the key intermediate 1, among which fluoro-neplanocin A was found to be novel mechanism-based irreversible inhibitor of S-Adenosylhomocysteine hydrolase. [ABSTRACT FROM AUTHOR]

Improved and alternative syntheses of d- and l-cyclopentenone derivatives were achieved in six steps from d-ribose via ring-closing metathesis (RCM) reaction as a key step. These derivatives serve as very versatile intermediates for the synthesis of carbocyclic nucleosides. [Copyright &y& Elsevier]

On the basis of the bioisosteric rationale to apio dideoxynucleosides, novel thioapio dideoxynucleosides have been synthesized, starting from 1,3-dihydroxyacetone via thioapio sugar acetate as a key intermediate. The intermediate was condensed with silylated pyrimidine bases such as N4-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the β-anomers (, , and ) and α-anomers (, , and ), respectively. The intermediate was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives and which were converted to adenine derivatives and , N6-methyladenine derivatives and , and hypoxanthine derivatives and , respectively. The guanine analogues and were also synthesized from the condensation of sugar acetate with 2-acetamido-6-chloropurine. All synthesized final compounds were tested against HIV-1. Most of the synthesized compounds exhibited toxicity-dependent anti-HIV-1 activity, among which 6-chloropurine derivative was found to be the most cytotoxic and showed good cytotoxicity against colon cancer cell lines. Although we could not find good anti-HIV agents in this study, findings of some anticancer activity in this series will allow this class of nucleosides to be the new template for the development of new anticancer agents (Fig. 1Figure 1). [Copyright &y& Elsevier]

Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1–15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 μM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver–Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition. [ABSTRACT FROM AUTHOR]

Abstract: A preparative and short synthesis of l-ribose and l-apiose was accomplished starting from d-ribose via stereoselective cis-dihydroxylation and C2-hydroxymethylation, respectively. These l-sugars can serve as versatile intermediates for the synthesis of l-nucleosides. [Copyright &y& Elsevier]

A novel apio analogue of neplanocin A was efficiently synthesized from D-ribose via stereoselective aldol-retroaldol reaction for introducing hydroxymethyl group and RCM reaction for synthesizing carbocycle, and its inhibitory activity against SAH hydrolase was assayed. [ABSTRACT FROM AUTHOR]

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1–8 were prepared as potential tyrosinase inhibitors. Four analogs (1–3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders. [ABSTRACT FROM AUTHOR]

(Z)-5-Benzylidene-2-phenylthiazol-4(5H)-one ((Z)-BPT) derivatives were designed by combining the structural characteristics of two tyrosinase inhibitors. The double-bond geometry of trisubstituted alkenes, (Z)-BPTs 1–14, was determined based on the 3JC,Hβ coupling constant of 1H-coupled 13C NMR spectra. Three (Z)-BPT derivatives (1–3) showed stronger tyrosinase inhibitory activities than kojic acid; in particular, 2 was to be 189-fold more potent than kojic acid. Kinetic analysis using mushroom tyrosinase indicated that 1 and 2 were competitive inhibitors, whereas 3 was a mixed-type inhibitor. The in silico results revealed that 1–3 could strongly bind to the active sites of mushroom and human tyrosinases, supporting the kinetic results. Derivatives 1 and 2 decreased the intracellular melanin contents in a concentration-dependent manner in B16F10 cells, and their anti-melanogenic efficacy exceeded that of kojic acid. The anti-tyrosinase activity of 1 and 2 in B16F10 cells was similar to their anti-melanogenic effects, suggesting that their anti-melanogenic effects were primarily owing to their anti-tyrosinase activity. Western blotting of B16F10 cells revealed that the derivatives 1 and 2 inhibited tyrosinase expression, which partially contributes to their anti-melanogenic ability. Several derivatives, including 2 and 3, exhibited potent antioxidant activities against ABTS cation radicals, DPPH radicals, ROS, and peroxynitrite. These results suggest that (Z)-BPT derivatives 1 and 2 have promising potential as novel anti-melanogenic agents. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor (PPAR) nuclear receptor has been an interesting target for the treatment of chronic diseases. Although the efficacy of PPAR pan agonists in several metabolic diseases has been well studied, the effect of PPAR pan agonists on kidney fibrosis development has not been demonstrated. To evaluate the effect of the PPAR pan agonist MHY2013, a folic acid (FA)-induced in vivo kidney fibrosis model was used. MHY2013 treatment significantly controlled decline in kidney function, tubule dilation, and FA-induced kidney damage. The extent of fibrosis determined using biochemical and histological methods showed that MHY2013 effectively blocked the development of fibrosis. Pro-inflammatory responses, including cytokine and chemokine expression, inflammatory cell infiltration, and NF-κB activation, were all reduced with MHY2013 treatment. To demonstrate the anti-fibrotic and anti-inflammatory mechanisms of MHY2013, in vitro studies were conducted using NRK49F kidney fibroblasts and NRK52E kidney epithelial cells. In the NRK49F kidney fibroblasts, MHY2013 treatment significantly reduced TGF-β-induced fibroblast activation. The gene and protein expressions of collagen I and α-smooth muscle actin were significantly reduced with MHY2013 treatment. Using PPAR transfection, we found that PPARγ played a major role in blocking fibroblast activation. In addition, MHY2013 significantly reduced LPS-induced NF-κB activation and chemokine expression mainly through PPARβ activation. Taken together, our results suggest that administration of the PPAR pan agonist effectively prevented renal fibrosis in both in vitro and in vivo models of kidney fibrosis, implicating the therapeutic potential of PPAR agonists against chronic kidney diseases. [ABSTRACT FROM AUTHOR]

In this study, (Z)-2-(benzylamino)-5-benzylidenethiazol-4(5H)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((Z)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5H)-one [7] and (Z)-2-(benzylamino)-5-(2,4-dihydroxybenzylidene)thiazol-4(5H)-one [8]) showed more potent mushroom tyrosinase inhibitory activities than kojic acid, regardless of the substrate used; in particular, compound 8 was 106-fold more potent than kojic acid when l-tyrosine was used as the substrate. Analysis of Lineweaver–Burk plots for 7 and 8 indicated that they were competitive inhibitors, which was confirmed via in silico docking. In experiments using B16F10 cells, 8 exerted a greater ability to inhibit melanin production than kojic acid, and it inhibited cellular tyrosinase activity in a concentration-dependent manner, indicating that the anti-melanogenic effect of 8 is attributable to its ability to inhibit tyrosinase. In addition, 8 exhibited strong antioxidant activity to scavenge 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and peroxynitrite and inhibited the expression of melanogenesis-associated proteins (tyrosinase and microphthalmia-associated transcription factor). These results suggest that BABT derivative 8 is a promising candidate for the treatment of hyperpigmentation-related diseases, owing to its inhibition of melanogenesis-associated protein expression, direct tyrosinase inhibition, and antioxidant activity. [ABSTRACT FROM AUTHOR]

Background: The protein kinase A (PKA)/cAMP response element-binding protein (CREB) has been suggested to be related to the inhibition of the proliferation of non-small cell lung cancer (NSCLC) cells. This study aimed to investigate the efficacy of a novel diarylcyclohexanone derivative, MHY4571, in regulating the PKA-CREB pathway and to study its anti-tumor role in squamous NSCLC. Methods: We designed MHY4571 as a novel PKA inhibitor with acceptable in silico ADME properties and tested it in vitro in lung cancer cell lines and in vivo in xenograft and orthotopic mouse models of squamous cell lung carcinoma. Results: MHY4571 inhibited PKA activity (> 70% inhibition) and suppressed the expression of p-PKA and p-CREB dose-dependently. MHY4571 treatment reduced lung cancer cell viability and promoted caspase 3-dependent apoptotic cell death. Orally administered MHY4571 significantly suppressed lung tumor growth in xenograft and orthotopic mouse models. PKA catalytic subunit alpha-silencing by siRNA (siPKA) strongly attenuated CREB phosphorylation; siCREB did not alter PKA protein levels or its phosphorylation, suggesting that PKA is an upstream regulator of CREB activity. MHY4571 acted synergistically with cisplatin (on co-treatment) to induce apoptotic cell death in lung cancer cells. Conclusions: Our results imply that MHY4571 may be a potential drug candidate for squamous cell lung cancer treatment. [ABSTRACT FROM AUTHOR]

Although various local anti-inflammatory therapies for ulcerative colitis have been developed, rapid drug elimination from inflamed colitis tissue and off-target side effects reduce their therapeutic efficacy. In this study, we synthesized curcumin (Cur)-loaded hyaluronic acid (HA)-conjugated nanoparticles (Cur-HA-PLGA-NPs) that target inflamed colitis tissue via HA-CD44 interaction with resident colonic epithelial cells and subsequently target activated macrophages for ulcerative colitis therapy. The synthesized spherical Cur-HA-PLGA-NPs showed physicochemical properties similar to those of non-HA-conjugated Cur-PLGA-NPs. HA-PLGA-NPs exhibited selective accumulation in inflamed colitis tissue with minimal accumulation in healthy colon tissue. HA functionalization enhanced targeted drug delivery to intestinal macrophages, significantly increasing HA-PLGA-NP cellular uptake. Importantly, the rectal administration of Cur-HA-PLGA-NPs exhibited better therapeutic efficacy than Cur-PLGA-NPs in animal studies. Histological examination revealed that Cur-HA-PLGA-NPs reduced inflammation with less inflammatory cell infiltration and accelerated recovery with re-epithelialization signs. Our results suggest that Cur-HA-PLGA-NPs are a promising delivery platform for treating ulcerative colitis. [ABSTRACT FROM AUTHOR]

[Display omitted] • 2-MBO analogs showed stronger tyrosinase inhibition potency than phenylthiourea. • In B16F10 cells, 2-MBO analogs strongly inhibited melanin production. • Their anti-melanogenic effect was due to inhibition of cellular tyrosinase activity. • Their tyrosinase inhibitory activity was due to chelation of tyrosinase copper ions. • 2-MBO analogs are promising candidates for treating skin-pigmentation disorders. Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs 1 – 3 exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC 50) values of 80–90 nM for l -dopa and 100–240 nM for l -tyrosine. Analogs 2 , 4 , and 5 showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO 4 demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity. [ABSTRACT FROM AUTHOR]

Abstract: On the basis of potent anti-HCV activity of 2′-C-methyladenosine, novel 2′-C-hydroxymethyladenosine analogues 2a–c were synthesized from d-ribose in order to lead to favorable interaction with HCV polymerase. Among compounds tested, adenosine derivative 2a exhibited potent anti-HCV activity, indicating that the hydroxyl group of 2′-C-hydroxymethyl substituent led to favorable interaction with HCV polymerase. [Copyright &y& Elsevier]

We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A3 AR expressed in CHO cells. Both 2′- and 3′-hydroxyl groups in the ribose moiety contribute to A3 AR binding and activation, with 2′-OH being more essential. Thus, the 2′-fluoro substitution eliminated both binding and activation, while a 3′-fluoro substitution led to only a partial reduction of potency and efficacy at the A3 AR. A 5′-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3′-fluoro derivatives. The 4′-thio substitution, which generally enhanced A3 AR potency and selectivity, resulted in 5′-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3-iodobenzyl)adenine moiety from the 1′- to 4′-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki=4.3 nM). Compound 16 antagonized human A3 AR agonist-induced inhibition of cyclic AMP with a KB value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A3 ARs. [Copyright &y& Elsevier]

The present work describes the asymmetric synthesis of d- and l-apio-2′,3′-dideoxynucleoside analogues, 4 and 5 with 2′-hydroxyl group via a common intermediate 9, starting from d-galactose. Stereoselective dihydroxylation and deoxygenation through radical inversion were successfully employed to synthesize the key intermediate 12 with d-apio structure, while stereoselecetive hydroboration-oxidation was used for the synthesis of another key intermediate 18 with l-apio structure. [Copyright &y& Elsevier]

Synthesis of 2′-deoxy-2′-fluoro-N6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A3 adenosine receptor are described. [ABSTRACT FROM AUTHOR]

Several 3′-fluoro analogues, 1a, 1b, and 1c of selective and potent adenosine A3 receptor agonist, Cl-IB-MECA were synthesized from d-xylose via highly regioselective opening of lyxo-epoxides, 8a and 8b with fluoride anion. Compared to the high binding affinity of Cl-IB-MECA to the A3 adenosine receptor, the corresponding 3′-fluoro derivative showed remarkably decreased binding affinity, indicating that 3′-hydroxyl group acts as hydrogen bonding acceptor, not hydrogen bonding donor like fluorine atom in binding to the A3 adenosine receptor. [Copyright &y& Elsevier]

Novel d-2′-azido-2′,3′-dideoxyarabinofuranosyl-4′-thiopyrimidines and purines have been synthesized, starting from l-xylose via azidation at the 2′-position as a key step. Most of the final nucleosides exhibited toxicity-dependent anti-HIV-1 activity, among which d-α-adenine analogue was found to be the most cytotoxic. [Copyright &y& Elsevier]

Tyrosinase plays an essential role in melanin biosynthesis, and as such it has received great attention as a key target for the treatment of pigmentation disorders. In our earlier studies, we explored analogs with the β‐phenyl‐α,β‐unsaturated carbonyl template, and the results obtained indicated that this template confers potent tyrosinase inhibitory activity. Thus, in the present study, (E)‐2‐(substituted benzylidene)‐3,4‐dihydronaphthalen‐1(2H)‐one derivatives (compounds 1–6) with this template were synthesized and investigated with respect to their mushroom tyrosinase inhibitory effects. Derivative 4 with a 3‐hydroxy‐4‐methoxyl substituent on the β–phenyl ring of the template inhibited mushroom tyrosinase fourfold more than kojic acid (IC50 = 15.60 ± 0.32 μM vs. 57.06 ± 0.46 μM). In silico docking simulation supported this potent inhibitory activity of compound 4 by demonstrating a binding energy of −6.4 kcal/mol at the active site of mushroom tyrosinase. Kinetic results imply that 4 competitively inhibits mushroom tyrosinase. [ABSTRACT FROM AUTHOR]

Age-associated renal fibrosis is commonly observed, with a decline in renal function during aging. Although peroxisome proliferator-activated receptors α/β (PPARα/β) activation has been shown to exert beneficial effects on age-associated renal changes, its effects on age-associated renal fibrosis have not been investigated yet. Here, we show that the PPARα/β activator, MHY2013, can significantly alter lipid metabolism in renal tubule epithelial cells and attenuate renal fibrosis in aged Sprague Dawley (SD) rats. We found that MHY2013 significantly increased nuclear translocation and activity of PPARα/β in NRK52E renal epithelial cells. Moreover, the enhanced PPARα/β activity increased the expression of fatty acid oxidation-associated PPARα/β target genes. In addition, transforming growth factor-β (TGF-β)- and oleic acid-induced lipid accumulation and fibrosis-associated gene expression were decreased in NRK52E cells by MHY2013 pretreatment. To evaluate the effects of MHY2013 on age-associated renal fibrosis, aged SD rates were orally administered MHY2013 (1 and 5 mg/kg) daily for 1 month. MHY2013 efficiently increased PPARα/β activation and reduced renal lipid accumulation in aged SD rat kidneys. Furthermore, renal fibrosis was significantly decreased by MHY2013, indicating the importance of renal lipid metabolism in age-associated renal fibrosis. Taken together, our results suggest that activation of PPARα/β signaling during aging prevents age-associated renal fibrosis. [ABSTRACT FROM AUTHOR]

Recently, 10 2-mercaptobenzo[ d ]imidazole (2-MBI) compounds (1 – 10) were synthesized. Although all 2-MBI compounds are tyrosinase inhibitors that inhibit mushroom tyrosinase at extremely low concentrations (IC 50 values: 20–740 nM) and effectively inhibit the browning of apples, to our knowledge, no studies have determined whether 2-MBI compounds inhibit mammalian tyrosinase. Mammalian tyrosinase is different from mushroom tyrosinase in its distribution within the cell and has structural characteristics that are different from mushroom tyrosinase in amino acid sequence and in the presence of a quaternary structure. Thus, the effect of the 10 2-MBI compounds on mammalian tyrosinase activity was investigated in B16F10 cells. Six compounds (1 – 6) exhibited stronger intracellular tyrosinase inhibition than that of kojic acid and phenylthiourea (PTU), which are known to be the most potent tyrosinase inhibitors; their strong tyrosinase inhibitory activity robustly inhibited intracellular melanin production in B16F10 cells. None of the tested 2-MBI compounds exhibited appreciable cytotoxicity in HaCaT and B16F10 cells. To confirm the anti -melanogenic efficacy of the 2-MBI compounds in vivo , a zebrafish embryo model was used. At concentrations 100 times lower than kojic acid, most 2-MBI compounds demonstrated much stronger depigmentation efficacy than that of kojic acid, and three 2-MBI compounds (2 – 4) showed depigmentation activity similar to or more potent than that of PTU, resulting in nearly pigment-free zebrafish embryos. These results suggest that 2-MBI compounds may be potential therapeutic agents for hyperpigmentation-related disorders. [Display omitted] • 2-Mercaptobenzo[ d ]imidazole (2-MBI) derivatives (1 – 10) greatly inhibited mammalian cell tyrosinase in B16F10 cells. • Four 2-MBI derivatives inhibited intracellular melanin production in B16F10 cells more potently than kojic acid and PTU. • Depigmentation experiments of 2-MBI derivatives using zebrafish embryos resulted in pigment-free zebrafish embryos. • These 2-MBI derivatives did not exhibit significant cytotoxicity in B16F10 cells and HaCaT cells at concentrations ≤20 μM. • These results suggest that 2-MBI derivatives may be potential therapeutic agents for hyperpigmentation-related disorders. [ABSTRACT FROM AUTHOR]

The aim of this study was to design and synthesize COX-1/COX-2 balanced inhibitors incorporating the structural motifs of anti-inflammatory ascidian metabolites. We designed a series of substituted indole analogs that incorporate the key structures of the ascidian metabolites, herdmanines C and D. The synthesized analogs were tested for their inhibitory activity against COX-1 and COX-2, and compound 5m , which displayed balanced inhibition, was further evaluated for in vitro anti-inflammatory activity. Compound 5m suppressed the expression of pro-inflammatory factors, including iNOS, COX-2, TNF-α, and IL-6 in LPS-stimulated murine RAW264.7 macrophages. The reduction of PGE 2 , NO, and ROS was also observed, together with the suppression of NF-κB, IKK, and IκBα phosphorylation. Our results characterized 5m as a COX-1/COX-2 balanced inhibitor that subsequently caused ROS inhibition and NF-κB suppression, and culminated in the suppression of iNOS, COX-2, TNF-α, and IL-6 expression. Image 1 • New balanced cyclooxygenase (COX-1 and COX-2) inhibitors were designed based on anti-inflammatory ascidian metabolites. • l COX-1 and COX-2 inhibitory activity of these analogues was evaluated in vitro. • Compound 5m showed substantial anti-inflammatory activity via inhibition of the NF-κB (nuclear factor-kappa B) pathway. [ABSTRACT FROM AUTHOR]

• Ten NAB derivatives were synthesized via Horner-Wadsworth-Emmons olefination. • 1a and 1j exhibited potent anti-melanogenic effects compared to kojic acid. • 1a and 1j showed stronger binding affinities for tyrosinase than kojic acid. Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N -(acryloyl)benzamide) derivatives (1a–1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ± 2.14% inhibition) and 1j (25.99 ± 2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ± 2.93% inhibition), and docking studies indicated 1a (−6.9 kcal/mole) and 1j (−7.5 kcal/mole) had stronger binding affinities for tyrosinase than kojic acid (−5.7 kcal/mole). At a concentration of 25 μM, 1a and 1j were nontoxic in B16F10 melanoma cells and exhibited stronger tyrosinase inhibition (59.70% and 76.77%, respectively) than kojic acid (50.30% inhibition) or arbutin (41.78% inhibition at 400 μM). Similarly, in B16F10 melanoma cells, compounds 1a and 1j at 25 μM decreased total melanin content by 47.97% and 61.77%, respectively (kojic acid; 38.98%). Similarities between inhibitions of tyrosinase activity and melanin contents suggested the anti-melanogenic effects of 1a and 1j were due to tyrosinase inhibition. The excellent DPPH scavenging activity of 1j suggests it might enhance in vivo effect on melanin contents. The study suggests compound 1j offers a potential starting point for the development of safe, potent tyrosinase inhibitors. [ABSTRACT FROM AUTHOR]

The induction of apoptosis is a useful strategy in anti-cancer research. Various Moon Hyung Yang (MHY) compounds have been developed as novel anti-cancer drug candidates; in the present study, the pro-apoptotic effects of (Z)-5-(3-ethoxy-4- hydroxybenzylidene)-2-thioxothiazolidin-4-one (MHY695) on HCT116 human colon cancer cells were assessed. MTT assays were performed to investigate the dose-dependent cytotoxic effects of MHY695 on HCT116 cells. Immunofluorescence staining and flow cytometry analyses were performed to identify apoptotic cell death, and western blot analysis was used to investigate the apoptotic-signaling pathways. A mouse xenograft model was also used to determine the effects of MHY695 in vivo. MHY695 decreased the viability of HCT116 cells and induced apoptotic cytotoxicity. The apoptotic mechanisms induced by MHY695 involved the dephosphorylation of Bcl-2-associated agonist of cell death protein following protein kinase B inactivation, induced myeloid leukaemia cell differentiation protein and BH3-interacting domain death agonist truncation, caspase-3 and −9 activation and poly (ADP-ribose) polymerase cleavage. In addition, MHY695 significantly suppressed tumor growth in the mouse xenograft model, compared with the vehicle control. Notably, MHY695 exhibited potent anti-cancer effects in four different types of human colon cancer cell line, including Caco-2, DLD-1, HT-29 and HCT116. Additionally, MHY695 showed reduced cytotoxicity in NCM460, normal colonic epithelial cells. Furthermore, MHY-induced cytotoxicity in colon cancer cells was independent of the tumor suppressor protein p53. Collectively, these observations suggested that MHY695 may be a novel drug for the treatment of colon cancer. [ABSTRACT FROM AUTHOR]

• Twenty cinnamamide derivatives were synthesized as potential tyrosinase inhibitors. • Four cinnmamides exhibited over 90% mushroom tyrosinase inhibitions than kojic acid. • In B16F10 cells, four compounds strongly decreased tyrosinase activity and melanin. • In docking study, four cinnamamides bind to tyrosinase strongerly than kojic acid. Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids' structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4 , 9 , 14 , and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 µM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the β-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 – 79.67% inhibition) at 25 μM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) < cyclohexylamino (19) < N -methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 μM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders. [ABSTRACT FROM AUTHOR]

• Fifteen 2,3-DPA derivatives were designed and synthesized via Perkin reaction. • (Z)-2,3-DPA derivative (1l′) was reported for the first time as a major product. • Mushroom tyrosinase and B16F10 cells were used for in vitro studies. • 1c significantly decreased the activity of mushroom and cellular tyrosinase. • In docking studies, 1c strongly binds to tyrosinase than kojic acid. During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-β-phenyl-α,β-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a – 1n and one (Z)-2,3-DPA-derivative 1l′ using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ± 3.53%, IC 50 = 20.04 ± 1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ± 2.93%, IC 50 = 30.64 ± 1.27 μM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (−7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (−5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 μM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 μM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents. [ABSTRACT FROM AUTHOR]

Tyrosinase is a key enzyme that catalyses the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC50 value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis. [ABSTRACT FROM AUTHOR]

Highlight • MHY908 attenuated MPTP-induced motor deficits and dopaminergic neuronal death. • MHY908 also ameliorated MPTP-induced glial activation in the STR and SN. • MHY908 pretreatment protected SH-SY5Y neuroblastoma cells against MPP+ toxicity. • Pretreatment of MHY908 inhibited MPP+-induced ROS generation. • MHY908 treatment attenuated MPP+-induced primary astrocyte activation and nuclear translocation of NF-κB. Abstract Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract Of the three enzymes that regulate the biosynthesis of melanin, tyrosinase and its related proteins TYRP-1 and TYRP-2, tyrosinase is the most important because of its ability to limit the rate of melanin production in melanocytes. For treating skin pigmentation disorders caused by an excess of melanin, the inhibition of tyrosinase enzyme is by far the most established strategy. Cinnamic acid is a safe natural product with an (E)-β-phenyl-α,β-unsaturated carbonyl motif that we have previously shown to play an important role in high tyrosinase inhibition. Since cinnamic acid is relatively hydrophilic, which hinders its absorption on the skin, fifteen less hydrophilic cinnamic amide derivatives (1 – 15) were designed as safe and more potent tyrosinase inhibitors and were synthesized through a Horner-Wadsworth-Emmons reaction. The use of conc -HCl and acetic acid for debenzylation of the O -benzyl-protected cinnamic amides 40 – 54 produced the following three results. 1) Cinnamic amides 43 , 48 , and 53 with a 2,4-dibenzyloxyphenyl group, irrespective of the amine type of the amides, produced complex compounds with high polarity. 2) Cinnamic amides 40 – 42 , 44 , 50 – 52 , and 54 with a benzylamino, or diethylamino group produced the desired debenzylated cinnamic amides 1 – 3 , 5 , 10 – 13 , and 15. 3) Cinnamic amides 45 – 47 , and 49 with an anilino moiety provided 3,4-dihydroquinolinones 16 – 19 through intramolecular Michael addition of the anilide group. Notably, the use of BBr 3 as an alternative debenzylating agent for debenzylation of cinnamic amides 45 – 49 with the anilino moiety provided our desired cinnamic amides 6 – 10 without inducing the intramolecular Michael addition. Debenzylation of cinnamic amides 43 , 48 , and 53 with a 2,4-dibenzyloxyphenyl group was also successfully accomplished using BBr 3 to give 4 , 9 , and 14. Among the nine compounds that inhibited mushroom tyrosinase more potently at 25 μM than kojic acid, four cinnamic amides 4 , 5 , 9 , and 14 showed 3-fold greater tyrosinase inhibitory activity than kojic acid. The docking simulation using tyrosinase indicated that these four cinnamic amides (−6.2 to −7.9 kcal/mol) bind to the active site of tyrosinase with stronger binding affinity than kojic acid (−5.7 kcal/mol). All four cinnamic amides inhibited melanogenesis and tyrosinase activity more potently than kojic acid in α-MSH-stimulated B16F10 melanoma cells in a dose-dependent manner without cytotoxicity. The strong correlation between tyrosinase activity and melanin content suggests that the anti-melanogenic effect of cinnamic amides is due to tyrosinase inhibitory activity. Considering that the cinnamic amides 4 , 9 , and 14 , which exhibited strong inhibition on mushroom tyrosinase and potent anti-melanogenic effect in B16F10 cells, commonly have a 2,4-dihydroxyphenyl substituent, the 2,4-dihydroxyphenyl substituent appears to be essential for high anti-melanogenesis. These results support the potential of these four cinnamic amides as novel and potent tyrosinase inhibitors for use as therapeutic agents with safe skin-lightening efficiency. Graphical abstract Image 1 Highlights • Fifteen cinnamic amide derivatives were designed and synthesized via Horner-Wadsworth-Emmons reaction. • Their anti-melanogenic effect were evaluated in mushroom tyrosinase and α-MSH-stimulated B16F10 melanoma cells. • Compound 4 , 5 , 9 and 14 revealed excellent anti-melanogenic effect as compared to kojic acid, used as positive control. • The docking study expressed that cinnamic amides bind to the active site of tyrosinase with strong binding affinity. [ABSTRACT FROM AUTHOR]

[Display omitted] • The 5-alkenyl-2-benzylaminothiazol-4(5 H)-ones 1 – 14 were synthesized as anti-melanogenic agents. via a rearrangement reaction. • Two analogs showed stronger mushroom tyrosinase inhibitory activity in the presence of l -tyrosine and l -dopa than kojic acid. • Kinetic studies indicated that 6 and 9 are a mixed type inhibitor and a competitive inhibitor, respectively. • In B16F10 murine cells, 6 and 9 effectively decreased melanin contents due to their ability to inhibit tyrosinase. • Considering strong antioxidant capacities, analogs 6 and 9 are potent anti-melanogenic agents with antioxidant ability. Mushroom tyrosinase is a tetramer, whereas mammalian tyrosinase is a monomeric glycoprotein. In addition, the amino acid sequence of mushroom tyrosinases differs from that of mammalian tyrosinases. MHY2081 exhibits potent inhibitory activity against both mushroom and mammalian tyrosinases. Accordingly, based on the MHY2081 structure, 5-alkenyl-2-benzylaminothiazol-4(5 H)-one analogs were designed as a novel anti-tyrosinase agent and synthesized using 2-((3,4-dimethoxybenzyl)amino)thiazol-4(5 H)-one (16), a key intermediate obtained via the rearrangement of a benzylamino group. Compounds 6 and 9 (IC 50 = 1.5–4.6 µM) exhibited higher mushroom tyrosinase inhibitory activity than kojic acid (IC 50 = 20–21 µM) in the presence of l -tyrosine and/or l -dopa. Based on kinetic analysis using Lineweaver-Burk plots, 6 was a mixed inhibitor, whereas 9 was a competitive inhibitor, and docking simulation results supported that these compounds could bind to the active site of mushroom tyrosinase. Using B16F10 mammalian cells, we demonstrated that these compounds inhibited melanogenesis more potently than kojic acid, and their anti-melanogenic effects could be attributed to tyrosinase inhibition. All synthesized compounds could scavenge reactive oxygen species (ROS), with five compounds exhibiting mild-to-strong ABTS+ and DPPH radical-scavenging abilities. Compounds 6 and 9 were potent tyrosinase inhibitors with strong antioxidant activities against ROS, ABTS+, and DPPH radicals. Moreover, the compounds significantly suppressed tyrosinase expression in a dose-dependent manner. Collectively, these results suggest that the novel 5-alkenyl-2-benzylaminothiazol-4(5 H)-one analogs, especially 6 and 9 , are potential anti-melanogenic agents with antioxidant activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4 , 9 , and 10 , bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents. [ABSTRACT FROM AUTHOR]

Abstract In a previous study, we synthesized endocyclic enone jasmonate derivatives that function as anti-inflammatory and PPAR-γ-activating entities by using key functional moieties of anti-inflammatory algal metabolites. Herein, we designed additional derivatives containing an exocyclic enone moiety that resembles the key structure of the natural PPAR-γ ligand, 15-deoxy-Δ12, 14-prostaglandin J 2 (15 d-PGJ 2). The exocyclic enone moiety of 15 d-PGJ 2 is essential for covalent bonding with the Cys285 residue in the PPAR-γ ligand-binding domain (LBD). In silico analysis of the designed compounds indicated that they may form hydrogen bonds with key amino acid residues in the PPAR-γ LBD, and thus, secure a position in the bioactive cavity in a similar fashion as does rosiglitazone and 15 d-PGJ 2. By a luciferase reporter assay on rat liver Ac2F cells, the synthesized compounds were evaluated for PPAR-γ transcriptional activity. The differential PPAR-γ transcriptional activities of the geometric and enantiomeric isomers of the selected analog were also evaluated; based on our results, the enantiopure compound (+)-(R,E)- 6a1 was suggested as a potential PPAR-γ ligand. Graphical abstract Image 1 Highlights • New PPAR-γ ligands were designed based on algal metabolites and endogenous ligand. • Synthetic analogs were evaluated for PPAR-γ activation by luciferase reporter assay. • The stereoisomers of the selected analog were compared for PPAR-γ activation. • (+)-(R , E)- 6a1 was proposed as a potential PPAR-γ agonist. [ABSTRACT FROM AUTHOR]

As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a - 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a β-phenyl-α,β-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC50 = 2.87 μM and 8.06 μM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC50 = 15.59 and 31.61 μM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates α-melanocyte-stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening. [ABSTRACT FROM AUTHOR]

The NAD + -dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1 month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233. In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance. [ABSTRACT FROM AUTHOR]

[Display omitted] Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17 , a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17 , 18 , and 22 will likely be of pharmacological utility. [ABSTRACT FROM AUTHOR]

Viriditoxin is a fungal secondary metabolite of the fungus Paecilomyces variotii derived from the inner tissues of the giant jellyfish Nemopilema nomurai. Viriditoxin exhibits antibacterial activity against Streptococcus iniae and Streptococcus parauberis , which are major pathogens of aqua cultured fish. Viriditoxin induced abnormal cell morphologies in the fish pathogens S. iniae and S. parauberis, presumably by inhibiting FtsZ polymerization as was previously observed in Escherichia coli . Synthetic analogues of viriditoxin, designed based on docking simulation results to FtsZ of Staphylococcus aureus , were prepared and compared with viriditoxin for antibacterial activity. Reconstitution of free hydroxyl or carboxyl groups of the methoxyl or methyl ester groups of viriditoxin led to significant reduction of antibacterial activity, implying that the natural molecule is optimized for antibacterial activity to deter bacteria potentially harmful to Paecilomyces . [ABSTRACT FROM AUTHOR]

2-[4-(5-Chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908) has been shown to prevent insulin resistance-induced hyperinsulinemia in aged rats. However, the mechanism underlying MHY908-mediated amelioration of renal inflammation with insulin resistance during aging remains unknown. This study investigated the effects of MHY908 on age-related changes in the IRS/Akt/forkhead box (FoxO) 1 signaling pathway in the kidneys of aged rats and HEK293T cells. Experiments were performed in young, old, and MHY908-fed old rats (1 mg or 3 mg/kg/day MHY908 for 4 weeks). We found that MHY908-fed old rats suppressed phosphorylation of IRS/Akt and induced FoxO1 activation, leading to increased expression of MnSOD and catalase. In addition, in insulin-treated cells, MHY908 prevented the FoxO1 inactivation and increased the expression of MnSOD and catalase by inactivating IRS and Akt. In contrast, NF-κB signaling pathway decreased with MHY908 treatment in insulin-treated cells. Furthermore, MHY908 exclusively activated peroxisome proliferator-activated receptor (PPAR) α in the kidneys, leading to the inhibition of insulin-induced NADPH oxidase subunit 4 (NOX4)-derived reactive oxygen species (ROS) generation and FoxO1 inactivation. In conclusion, MHY908 improved the hyperinsulinemia-induced pro-inflammatory response through NF-κB inactivation and FoxO1 activation in aged rat kidneys. These phenomena suggest that PPARα activation by MHY908 attenuates NOX4-derived ROS generation in response to insulin. [ABSTRACT FROM AUTHOR]

In this study, we synthesized ( E )-2-cyano-3-(substituted phenyl)acrylamide ( CPA ) derivatives which possess a linear β-phenyl-α,β-unsaturated carbonyl scaffold and examined their inhibitory activities against tyrosinase. CPA analogs exerted inhibitory activity against mushroom tyrosinase. Results from the docking simulation indicated that CPA2 could bind directly to the active site of mushroom tyrosinase and the binding affinity of CPA2 for tyrosinase might be higher than that of kojic acid, a well-known potent tyrosinase inhibitor. In B16F10 cells, CPA2 significantly suppressed tyrosinase activity and melanogenesis in a dose-dependent manner. At the concentration of 25 μM, CPA2 exhibited tyrosinase inhibitory activity comparable to that of kojic acid with no cytotoxic effect. Results from the present study suggest that CPA2 bearing a linear β-phenyl-α,β-unsaturated carbonyl scaffold may be the potential candidate for treatment of diseases associated with hyperpigmentation and that a linear β-phenyl-α,β-unsaturated carbonyl scaffold might be closely related to potent tyrosinase inhibition. [ABSTRACT FROM AUTHOR]

Inhibition of translation initiation has emerging implications for the development of mechanism-based anticancer therapeutics. Phosphorylation of eIF2α is recognized as a key target that regulates the translation initiation cascade. Based on the bioisosteric replacement of urea-derived eIF2α phosphorylation activator 1 , a novel series of N -aryl- N′ -[4-(aryloxy)cyclohexyl]squaramide derivatives was designed and synthesized; their effects on the activation of eIF2α phosphorylation was assessed systematically. A brief structure–activity relationship analysis was established by stepwise structural optimization of the squaramide series. Subsequently, the antiproliferative activities of the selected analogues were determined in human leukemia K562 cells. We then identified 10 potent eIF2α phosphorylation activators with considerable anticancer activity. The most promising analogues 19 and 40 possessed higher cancer cell selectivity (SI = 6.16 and 4.83, respectively) than parent 1 (SI = 2.20). Finally, protein expression analysis revealed that compounds 19 and 40 induced eIF2α phosphorylation and its downstream effectors ATF4 and CHOP. [Display omitted] • A new series of squaramides was designed and synthesized by a bioisosteric approach. • Ten analogues induced p-eIF2α and antiproliferation in K562 cells with high IC 50 value. • 19 and 40 exhibited remarkably high selectivity index (6.16 and 4.83, respectively). • 19 and 40 increased the expression level of eIF2α downstream proteins, ATF and CHOP. [ABSTRACT FROM AUTHOR]

Abstract: Aims of the study: Extracts of Schisandra chinensis have been used as an anti-fatigue and tonic agent. Because chronic fatigue syndrome is related to inflammatory and oxidative stress, we assessed whether Schisandra chinensis has anti-inflammatory constituents and studied the effect of a novel α-cubebenoate isolated from Schisandra chinensis. Materials and methods: α-Cubebenoate was isolated from an extract of Schisandra chinensis fruits. The inductions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) by lipopolysaccharide (LPS) were quantified by RT-PCR and Western blotting in mouse peritoneal macrophages. Nitric oxide (NO) and prostaglandin E2 (PGE2) were also measured in the media by Griess reagent and EIA method. A mouse model of LPS-induced peritonitis was used to test the in vivo efficacy of α-cubebenoate. Results: α-Cubebenoate (5–10μg/ml) inhibited the inductions of iNOS and COX-2 in mouse peritoneal macrophages at the mRNA and protein levels. LPS-induced productions of NO and PGE2 were inhibited by α-cubebenoate (5–10μg/ml). In addition, α-cubebenoate inhibited the LPS-induced activation of JNK, but not those of ERK and p38 MAPK in mouse peritoneal macrophages. Furthermore, in the LPS-induced in vivo peritonitis model, α-cubebenoate (1mg/kg) strongly inhibited the accumulation of polymorph nuclear lymphocytes in the peritoneal cavity. Conclusion: α-Cubebenoate inhibited LPS-induced expression of iNOS and COX-2 in a concentration-dependent manner, thereby suppressing productions of NO and PGE2 in vitro in peritoneal macrophages. α-Cubebenoate also inhibited LPS-induced accumulation of polymorph nuclear lymphocytes in LPS-induced peritonitis model in vivo. α-Cubebenoate may act as an anti-fatigue constituent of Schisandra chinensis through anti-inflammation and could be of therapeutic use as a treatment for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Aims of the study: Extracts of Schisandra chinensis have been used as an anti-fatigue and tonic agent. Because chronic fatigue syndrome is related to inflammatory and oxidative stress, we assessed whether Schisandra chinensis has anti-inflammatory constituents and studied the effect of a novel α-cubebenoate isolated from Schisandra chinensis. Materials and methods: α-Cubebenoate was isolated from an extract of Schisandra chinensis fruits. The inductions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) by lipopolysaccharide (LPS) were quantified by RT-PCR and Western blotting in mouse peritoneal macrophages. Nitric oxide (NO) and prostaglandin E2 (PGE2) were also measured in the media by Griess reagent and EIA method. A mouse model of LPS-induced peritonitis was used to test the in vivo efficacy of α-cubebenoate. Results: α-Cubebenoate (5–10μg/ml) inhibited the inductions of iNOS and COX-2 in mouse peritoneal macrophages at the mRNA and protein levels. LPS-induced productions of NO and PGE2 were inhibited by α-cubebenoate (5–10μg/ml). In addition, α-cubebenoate inhibited the LPS-induced activation of JNK, but not those of ERK and p38 MAPK in mouse peritoneal macrophages. Furthermore, in the LPS-induced in vivo peritonitis model, α-cubebenoate (1mg/kg) strongly inhibited the accumulation of polymorph nuclear lymphocytes in the peritoneal cavity. Conclusion: α-Cubebenoate inhibited LPS-induced expression of iNOS and COX-2 in a concentration-dependent manner, thereby suppressing productions of NO and PGE2 in vitro in peritoneal macrophages. α-Cubebenoate also inhibited LPS-induced accumulation of polymorph nuclear lymphocytes in LPS-induced peritonitis model in vivo. α-Cubebenoate may act as an anti-fatigue constituent of Schisandra chinensis through anti-inflammation and could be of therapeutic use as a treatment for inflammatory diseases. [Copyright &y& Elsevier]

Abstract: The skin is the primary target of prolonged and repeated ultraviolet (UVB) irradiation which induces cutaneous inflammation and pigmentation. Nuclear factor κB (NF-κB) is the major factor mediating UVB-induced inflammatory responses through the expression of various proinflammatory proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). We have previously reported that the synthetic novel compound 4-(5-chloro-2,3-dihydrobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (MHY884) strongly suppressed tyrosinase activity and melanin synthesis in B16F10 melanoma cells. In the present study, we investigated the effect of MHY884 on the inhibition of UVB-induced NF-κB activation and its proinflammatory downstream proteins through the suppression of oxidative stress in an in vivo model of photoaging. Generation of reactive oxygen species (ROS) and peroxynitrite was measured in vitro and in B16F10 melanoma cells to verify the scavenging activity of MHY884. MHY884 suppressed oxidative stress both in vitro and in the melanoma cells in a dose-dependent manner. Next, melanin-possessing hairless mice were pre-treated with MHY884 and then irradiated with UVB repeatedly. Topical application of MHY884 attenuated UVB-induced oxidative stress, resulting in reduced NF-κB activity. Pre-treatment with MHY884 inhibited Akt and IκB kinase α/β signaling pathways, leading to decreased translocation and phosphorylation of p65, a subunit of NF-κB. This result correlated with the expression levels of iNOS and COX-2 in the skin of MHY884-treated mice. Thus, the novel tyrosinase inhibitor MHY884 suppressed NF-κB activation signaling pathway by scavenging UVB-induced oxidative stress. The discovery of MHY884, a novel tyrosinase inhibitor that targets NF-κB signaling, is significant, because this compound is a promising protective agent against UVB-induced skin damage. [Copyright &y& Elsevier]

• The solubility of efinaconazole in fifteen mono solvents was studied. • The solubility of efinaconazole in three solvents + water mixtures was determined. • Solvent effect on solubility of efinaconazole was described by using KAT-LSER model. • Various models were applied to correlate and fit the solubility data of efinaconazole. In this study, the solubility data of the solid–liquid equilibrium of efinaconazole in acetone, acetonitrile, 1-butanol, diethylene glycol monoethyl ether (DEGME), dichloromethane, dimethylformamide (DMF), ethanol, ethyl acetate, methanol, 1-propanol, 2-propanol, propylene glycol, polyethylene glycol 400 (PEG 400), tetrahydrofuran, water, and three binary mixed solvents (DEGME + water, ethanol + water, and PEG 400 + water) were measured at five different temperatures (288.15–308.15 K) using the shake-flask technique. The solubility of efinaconazole in the fifteen mono solvents was highest in dichloromethane, followed by tetrahydrofuran, DMF, and acetone, and lowest in water. In the binary mixtures, the solubility of efinaconazole increased with an increase in the DEGME, ethanol, and PEG 400 mass fraction at a defined temperature, respectively. According to the Kamlet-Taft linear solvation energy relationship model analysis, the self-cohesiveness of the solvent indicating solvent–solvent interaction was the main factor affecting the solubility of efinaconazole, which resulted in decreased solubility. Nine models, including the van't Hoff, modified Apelblat, Buchowski-Ksiazczak λh, simplified CNIBS/R-K, Jouyban-Acree, Jouyban-Acree-van't Hoff, Jouyban-Acree-modified Apelblat, Sun, and Ma models, were used to regress the experimental solubility data of efinaconazole in fifteen mono solvents and the three binary mixtures. In addition, the dissolution thermodynamic properties of efinaconazole were estimated using a modified van't Hoff analysis. The experimental solubility data and correlated models of efinaconazole in fifteen mono solvents and the three binary mixed solvents could be useful for the crystallization, purification, and development of liquid dosage forms such as topical solutions during drug development. [ABSTRACT FROM AUTHOR]