Search

1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound 5 ), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound 13 , featuring an oxopropyl group at the ortho -position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC 50 values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound 5 . Further mechanistic studies revealed that compound 13 significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.

Synthetic routes to geosmin and its enantiomer are well established, but the enantioselective synthesis of stereoisomers of geosmin is unknown. Here a stereoselective synthesis of all stereoisomers of geosmin is reported, yielding all compounds in high enantiomeric purity. Furthermore, the stereoselective synthesis of a geosmin derivative isolated from a mangrove associated streptomycete was performed, establishing the absolute configuration of the natural product. Finally, a new side product of the geosmin synthase from Streptomyces ambofaciens was isolated and its structure was elucidated by NMR spectroscopy. The absolute configuration of this new compound was determined through a stereoselective synthesis.

Cysteine (Cys) plays an indispensable role as an antioxidant in the maintenance of bioredox homeostasis. We have constructed an efficient fluorescent probe Mito-Cys based on the binding of indole and naphthol. The acrylic ester group serves as a recognition switch for specific detection of Cys, which undergoes Michael addition and intramolecular cyclization reactions, thereby ensuring the chemical kinetics priority of Cys compared to other biothiols. The probe has good water solubility, large Stokes shift (137 nm), with a detection limit of 21.81 nM. In addition, cell imaging experiments have shown that the probe has excellent mitochondrial targeting ability (R = 0.902). The probe can distinguish between Cys, homocysteine (Hcy) and glutathione (GSH), and can detect Cys specifically and quickly (100 s) to ensure accurate quantitative analysis of Cys changes in cells. More importantly, the probe confirms that ferroptosis inducing factors trigger thiol starvation in mitochondria, which helps to gain a deeper understanding of the physiological and pathological functions related to Cys and ferroptosis., (© 2024. The Author(s), under exclusive licence to the European Photochemistry Association, European Society for Photobiology.)

In this research, a new magnetic nanocomposite Fe 3 O 4 @Saponin/Cu(II) based on quillaja saponin was prepared and the catalyst structure was characterized thoroughly using FT-IR, EDS, TGA, XRD, VSM, HR-TEM, SEM, ICP, BET analyzes. The catalyst prepared in the three-component synthesis of several Betti bases, 1-(α-aminoalkyl)naphthols, under environmentally friendly conditions was used. The advantage of this reaction is the high efficiency of the products and the short reaction time. Furthermore, Fe 3 O 4 @Saponin/Cu(II) nano-catalyst is recoverable magnetically and is reusable for other processes with no reduction in its activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Melanosomes in nature have diverse morphologies, including spheres, rods, and platelets. By contrast, shapes of synthetic melanins have been almost entirely limited to spherical nanoparticles with few exceptions produced by complex templated synthetic methods. Here, we report a non-templated method to access synthetic melanins with a variety of architectures including spheres, sheets, and platelets. Three 1,8-dihydroxynaphthalene dimers (4-4', 2-4' and 2-2') were used as self-assembling synthons. These dimers pack to form well-defined structures of varying morphologies depending on the isomer. Specifically, distinctive ellipsoidal platelets can be obtained using 4-4' dimers. Solid-state polymerization of the preorganized dimers generates polymeric synthetic melanins while maintaining the initial particle morphologies. This work provides a new route to anisotropic synthetic melanins, where the building blocks are preorganized into specific shapes, followed by solid-state polymerization., (© 2021 Wiley-VCH GmbH.)

A series of some naphthol derivatives 4a-f, 5a,f, 6a, and 7a,b (six novel ones: 4c,d, 5a, 6a, 7a,b) bearing F, Cl, Br, OMe, and dioxole substituents at different positions of the aromatic rings was designed, synthesized, and characterized. The naphthol derivatives were synthesized in three steps, namely the addition reaction of furan via Diels-Alder cycloaddition reaction, copper(II) trifluoromethanesulfonate (Cu(OTf) 2 )-catalyzed aromatization reaction, and the bromination reaction, respectively. The structures of the newly obtained compounds (4c,d, 5a, 6a, 7a,b) were characterized by spectroscopic techniques. In addition, some biological activity studies were investigated under in vitro conditions. Inhibition studies of these compounds were performed on human carbonic anhydrase (hCA) I and II isoenzymes purified from human erythrocytes as a biological evaluation. Moreover, their potential antioxidant and antiradical activities were studied by analytical methods like ABTS •+ and DPPH• scavenging, and it was determined that some molecules showed good activity. Also, inhibition of acetylcholinesterase (AChE), which is a marker of many degenerative neurological diseases, was tested and the results were discussed. Excellent enzyme inhibition results were recorded for most of the molecules. These 1-naphthol derivatives were found as effective inhibitors for hCA I, hCA II, and AChE with K i values ranging from 0.034 ± 0.54 to 0.724 ± 0.18 µM for hCA I, 0.172 ± 0.02 to 0.562 ± 0.21 µM for hCA II, and 0.096 ± 0.01 to 0.177 ± 0.02 µM for AChE., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Background : G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods : Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b']dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results : The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI 50 in the low μM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions : The new series of naphtho[1,2-b:8,7-b']dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers.

To achieve a rapid and facile quantitative evaluation of Sudan I illegally added in ketchup, fluorescent carbon quantum dots with excellent stability in acidic environments are required as the actual pH value of ketchup is close to 4.0. In this paper, we developed a green approach to prepare sulfur-doped carbon quantum dots (SCQDs) via hydrothermal treatment of lignin, isolated from pre-hydrolysis liquor, in sulfuric acid solution. The resultant SCQDs from lignin possessed sulfur-containing groups, which exhibited excellent fluorescence with a quantum yield up to 13.5% and good stability in acidic environments with a wide pH range of 0-5.0. Therefore, the SCQDs were successfully employed as a sensor to detect Sudan I in acidic solutions with excellent selectivity and sensitivity. The linear range for Sudan I was 0-40 μM, while the limit of detection was 0.12 μM. In addition, the fluorescent indicator paper functionalized with SCQDs also showed outstanding selectivity to Sudan I. The proposed SCQD sensing system not only displayed application potential for quantitative evaluation of Sudan I dye in practical samples, but also provided a way to convert lignin-based waste into highly valued nanoscale materials.

Herein we report the stereochemical revision of peribysins A, B, C, F, and G, guided by enantiospecific total synthesis starting from (+)-nootkatone. Furthermore, we reconfirmed the absolute stereochemistry of peribysin Q. The highlights of the synthesis are enone transposition and kinetic iodination resulting in separation of diastereomers. Our findings coupled with synthetic and biological data previously reported by Danishefsky's group suggest that the original stereochemistries of peribysins A, B, C, F, and G were misassigned.

The biaryl scaffold, often showing axial chirality, is a common feature of various fungal natural products. Their biosynthesis requires an oxidative phenol-coupling reaction usually catalyzed by laccases, cytochrome P450 enzymes, or peroxidases. The combination of a laccase and a fasciclin domain-containing ( fas ) protein is encoded in many biosynthetic gene clusters of biaryls from ascomycetes. However, such phenol-coupling systems including their regio- and stereoselectivity have not been characterized so far. Elucidating the biosynthesis of the antiparasitic binaphthalene sporandol from Chrysosporium merdarium , we demonstrate the combination of a laccase and a fas protein to be crucial for the dimerization reaction. Only the heterologous coproduction of the laccase and the fas protein led to a functional phenol-coupling system, whereas the laccase alone showed no coupling activity. Thus, the laccase/ fas protein combination forms an independent group of phenol-coupling enzymes that determines the coupling activity and selectivity of the reaction concurrently and applies to the biosynthesis of many fungal natural products with a biaryl scaffold.

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[ d ]oxazole (ezutromid, 1 ) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

Several perylene (Pery)-doped 2-naphthol (2-NP) (Pery/2-NP) luminophors were prepared using conventional solid-state reaction techniques. Energy transfer in the excited state was examined using fluorescence spectroscopy and cyclic voltammetry. Fluorescence studies revealed exciplex formation by Pery in the form of structureless and broad spectra at higher concentrations with monomer quenching of 2-NP; a broad green emission was observed in the range 500-650 nm, peaking at 575 nm. Structural properties and thermal stability were analyzed using X-ray diffraction, scanning electron microscopy and TGA-differential scanning calorimetry. Highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels were observed in the range 5.56-5.61 eV and 2.79-2.81 eV, respectively with a 2.77-2.82 eV band gap. The present study reveals these to be probable candidates for hole-transporting materials suitable in optoelectronics., (© 2019 John Wiley & Sons, Ltd.)

An iron-catalyzed asymmetric oxidative homo-coupling of 2-naphthols for the synthesis of 1,1'-Bi-2-naphthol (BINOL) derivatives is reported. The coupling reaction provides enantioenriched BINOLs in good yields (up to 99%) and moderate enantioselectivities (up to 81:19 er) using an iron-complex generated in situ from Fe(ClO 4 ) 2 and a bisquinolyldiamine ligand [(1 R ,2 R )- N 1 , N 2 -di(quinolin-8-yl)cyclohexane-1,2-diamine, L1 ]. A number of ligands ( L2 - L8 ) and the analogs of L1 , with various substituents and chiral backbones, were synthesized and examined in the oxidative coupling reactions., Competing Interests: The authors declare no conflicts of interest.

We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue β-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C 2 -symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3'-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An efficient, clean and one-pot multicomponent synthesis of divers kind of new functionalized aminoalkyl naphthol and amidoalkyl naphthol derivatives via tandem condensation reaction of 2-naphthol, aromatic aldehydes and 5-methyl-1,3,4-thiadiazol-2-amine/5-aryl-1,3,4-thiadiazol-2-amines urea/acetamide under solvent-free conditions is reported. Following this protocol, it was possible to synthesize novel 1-(((5-methyl-1,3,4-thiadiazol-2-yl)amino)(aryl)methyl)naphthalen-2-ol, 1-(aryl((5-aryl-1,3,4-thiadiazol-2-yl)amino)methyl)naphthalen-2-ol and amidoalkyl naphthol derivatives. This protocol includes some salient features, such as the use of triethylammonium hydrogen sulfate ([Et 3 NH][HSO 4 ]) ionic liquid as a green, clean and reusable catalyst, no column chromatographic separation, high atom economy, good yields, low cost and finally no need for a complex procedure.

A direct optochemical method for regulating gene function has been developed based on uncaging of an inactive caged precursor that fragments to produce a CREB (cAMP-response element binding protein) inhibitor that binds to an endogenous transcription factor responsible for regulating CREB-mediated gene expression levels.

Background: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains., Objective: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains., Methods: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays., Results: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics., Conclusion: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of twenty-six methoxylated and methylated N -aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N -(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus as well as against Mycobacterium tuberculosis and M. kansasii . In addition, the inhibitory profile of photosynthetic electron transport in spinach ( Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N -(3,5-dimethylphenyl)-, N -(3-fluoro-5-methoxy-phenyl)- and N -(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k ), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure-activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.

o-Phenylazonaphthol (o-PAN) derivatives including 6-bromo-1-((4-bromophenyl)diazenyl)naphthalen-2-ol (AN-Br-OH) and 1-phenylazo-2-naphthol (AN-OH, known as Sudan I (Color Index 12055)) were synthesized to investigate their fluorogenic behaviors, in which their aggregated-induced emission (AIE) is reported. The o-PANs showed a two-photon absorption. The protection of hydroxyl groups in o-PANs was used for fluorescence imaging of esterase-expressed HepG2 cells, which is potentially suitable for sensing and two-photon cell imaging applications.

A convenient Rh(III)-catalyzed C-H activation and cascade [4+2] annulation for the synthesis of naphthalenone sulfoxonium ylides has been developed. This method features perfect regioselectivity, mild and redox-neutral reaction conditions, and broad substrate tolerance with good to excellent yields. Preliminary mechanistic experiments were conducted and a plausible reaction mechanism was proposed. The new type naphthalenone sulfoxonium ylides could be further transformed into multi-substituted naphthols, which demonstrates the practical utility of this methodology.

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

Nitroxyl (HNO), the one-electron-reduction product of NO has recently been revealed to have potentially beneficial pharmacological properties in cardiovascular health as a result of interactions with specific thiols such as glutathione (GSH). To disentangle the complicated inter-relationship between HNO and GSH in the signal transduction and oxidative pathways, we designed and synthesized a dual-site fluorescent probe NCF to indicate cellular HNO and GSH-GSSG balance. The sensitive and selective detection of HNO was achieved by incorporating an organophosphine group to naphthaldehyde-TCF. Then the resulted fluorescent product is able to monitor the conversion of GSH and GSSG reversibly. Additionally, outstanding biocompatibility make it capable of monitoring intracellular HNO and consequently GSH-GSSG oscillationsin living cells. We anticipate that NCF will be a unique molecular tool to investigate the interplaying roles of HNO and GSH.

An air- and moisture-stable molybdenum Schiff base complexes immobilized on magnetic iron oxide nanoparticles with a core-shell structure was developed for utilization as a new heterogeneous catalyst. The surface, structural and magnetic characteristics of the nanomaterials were characterized by using Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRD), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and inductively coupled plasma atomic emission spectroscopy (ICP-AES). In application point of view, an ultrasonic assisted one-pot multicomponent protocol for the synthesis of 1-(α-aminoalkyl)-2-naphthol derivatives have been demonstrated under mild condition with short reaction times, high yields and TON values up to 570. To survey the generality of the procedure, we studied the synthesis of α-aminonitrile derivatives with different aldehydes, trimethylsilyl cyanide (TMSCN) and aniline under the same conditions. Additionally, binding interaction of 1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-ol (AMAN-1) with various types of rigid DNA and HSA has been investigated by molecular modeling study. In vitro studies under physiological conditions showed that the desired derivative interacts with calf-thymus DNA (ct-DNA) via an intercalative binding mode., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Synthesis of noble metal nanoparticles (NPs) on modified graphene oxide with biocompatible polymers has attracted significant due to their unique properties and various applications. In this research, covalent-modified graphene oxide (MGO) with diacid terminated poly (ethylene glycol) (PEG) was used as a substrate and stabilizing of Au (ш). The reduction of MGO-Au (ш) complex with hydrazine monohydrate under reflux condition obtained biocompatible reduced MGO (rMGO)-Au NPs. Diacid terminated PEG obtained from the reaction of PEG with succinic anhydride in the presence of N,N- dicyclohexylcarbodiimide (DCC) and 4-methylamino pyridine (DMAP) was attached to GO sheets to prevent from the aggregation of rMGO sheets and Au NPs. The resulting aqueous suspension was characterized through UV-vis, FT-IR, Raman, XRD, DLS-zeta potential, SEM, EDX and TEM. Furthermore, nanocomposite showed good catalytic behavior in Betti reaction- synthesis of 1-(α-aminoalkyl)-2-naphthols. The favorable properties of colloidal nanocomposite were attributed to the stable and well distribution Au NPs on rMGO., (Copyright © 2018. Published by Elsevier B.V.)

A series of new pyrazole linked benzothiazole-β-naphthol derivatives were designed and synthesized using a simple, efficient and ecofriendly route under catalyst-free conditions in good to excellent yields. These derivatives were evaluated for their cytotoxicity on selected human cancer cell lines. Among those, the derivatives 4j, 4k and 4l exhibited considerable cytotoxicity with IC 50 values ranging between 4.63 and 5.54 µM against human cervical cancer cells (HeLa). Structure activity relationship was elucidated by varying different substituents on benzothiazoles and pyrazoles. Further, flow cytometric analysis revealed that these derivatives induced cell cycle arrest in G2/M phase and spectroscopic studies such as UV-visible, fluorescence and circular dichroism studies showed that these derivatives exhibited good DNA binding affinity. Additionally, these derivatives can effectively inhibit the topoisomerase I activity. Viscosity studies and molecular docking studies demonstrated that the derivatives bind with the minor groove of the DNA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A chiral amino alcohol based ligand was found to promote the highly enantioselective addition of terminal conjugated diynes to aromatic and aliphatic aldehydes. The combination of easily available C 2 -symmetric (R)- and (S)-BINOL with Ti(OiPr) 4 , Zn powder, and EtI was also found to catalyze the asymmetric addition of 1,3-diynes to aldehydes under mild reaction conditions, and thus, both enantiomers of the chiral conjugated diynols could be prepared with high enantioselectivities. The resulting optically active conjugated diynols were found to have potential anticancer activities with significant differences against HepG2 and HeLa cancer cells, and remarkable enantioselective cytotoxicity was observed for the first time., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work reports a combination of aryl diselenides/hydrogen peroxide and carbon-nanotube (CNT)/rhodium nanohybrids (RhCNT) for naphthol oxidation towards the synthesis of 1,4-naphthoquinones and evaluation of their relevant trypanocidal activity. Under a combination of (PhSe) 2 /H 2 O 2 in the presence of O 2 in iPrOH/hexane, several benzenoid (A-ring)-substituted quinones were prepared in moderate to high yields. We also studied the contribution of RhCNT as co-catalyst in this process and, in some cases, yields were improved. This method provides an efficient and versatile alternative for preparing A-ring-modified naphthoquinonoid compounds with relevant biological profile., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca by monitoring antioxidative activity using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Starting from a tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the stereochemistry of 1, we synthesized the natural product (±)-isolariciresinol (18) from alcohol 17. Comparison of the spectral data showed good agreement. Glycosylation was investigated using four different glycosyl donors. Only the Koenigs-Knorr condition using silver trifluoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection and purification using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC 50  = 34.4, 28.8, 53.0 μM, respectively.

Introduction: The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme., Results: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions., Conclusion: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure-based drug design efforts in HAT drug discovery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Heterogeneous metal catalysts constitute a very important tool for the synthesis of functional materials and fine chemicals owing to their high efficiency, robustness, and facile recyclability. Biaryls are privileged structural motifs in many natural products, chiral ligands, and catalysts. The oxidative biaryl coupling reaction is one of the most promising methods for biaryl synthesis in terms of atom and step economies. However, although oxidative biaryl coupling of naphthols has been studied thoroughly, the coupling of aryl amines providing biaryl amines like 2,2'-diamino-1,1'-binaphthyl (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives remains elusive. Recently, we have found that aryl amines are efficiently dimerized with the use of a heterogeneous Rh/C catalyst under acidic conditions. This heterogeneously catalyzed method can be adapted to the highly selective cross-coupling reaction of aryl amines and the intramolecular biaryl coupling reaction. Furthermore, we developed an aerobic direct C-H oxidation of polycyclic aromatics catalyzed by a recyclable heterogeneous rhodium catalyst. These methodologies are advantageous compared with the existing reactions owing to the mild aerobic conditions employed and the facile recyclability of the heterogeneous catalysts used.

Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach ( Spinacia oleracea L.) chloroplasts. 1-Hydroxy- N -phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC 50 = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P 680 and plastoquinone Q B in the PET chain occurring on the acceptor side of PS II can be suggested as the site of action of the compounds. The structure-activity relationships are discussed., Competing Interests: The authors declare no conflicts of interest.

Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the K i values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC 50 value. This shows that kinetic characterization of inhibitors and calculation of K i values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results., Results: Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC 50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC 50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5., Conclusion: We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

Estrogen receptors (ERs) are targets for endocrine treatment of estrogen-dependent cancers. The ER consists of 2 isoforms, ERα and ERβ, which have distinct biologic functions. Whereas activation of ERα stimulates cell proliferation and cell survival, ERβ promotes apoptosis. PET of ERα and ERβ levels could provide more insight in response to hormonal treatment. 16α- 18 F-fluoro-17β-estradiol ( 18 F-FES) is a PET tracer for ER with relative selectivity for ERα. Here we report the synthesis and evaluation of a potential ERβ-selective PET tracer: 2- 18 F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol ( 18 F-FHNP). Methods: 18 F-FHNP was synthesized by fluorination of the corresponding nitro precursor, followed by acidic removal of the 2-methoxyethoxymethyl protecting group. In vitro affinity of 18 F-FHNP and 18 F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies with 18 F-FHNP and 18 F-FES were conducted in athymic nude mice bearing a SKOV3 xenografts. Results: 18 F-FHNP had nanomolar affinity for ERs, with a 3.5 times higher affinity for ERβ. 18 F-FHNP was obtained in 15%-40% radiochemical yield (decay-corrected), with a specific activity of 279 ± 75 GBq/μmol. 18 F-FHNP had a dissociation constant of 2 nM and maximum binding capacity of 18 fmol/10 6 cells, and 18 F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/10 6 SKOV3 cells. Both 18 F-FHNP and 18 F-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of 18 F-FHNP and 18 F-FES in most peripheral organs. 18 F-FES showed a 2-fold-higher tumor uptake than 18 F-FHNP. The tumor-to-plasma ratio of 18 F-FES decreased 55% ( P = 0.024) and 8% ( P = 0.68) when administered in the presence of estradiol (nonselective) and genistein (ERβ-selective), respectively. The tumor-to-plasma ratio of 18 F-FHNP decreased 41% ( P = 0.004) and 64% ( P = 0.0009) when administered with estradiol and genistein, respectively. Conclusion: The new PET tracer 18 F-FHNP has suitable properties for imaging and shows relative selectivity for ERβ., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

The first total syntheses of aflavazole (6) and 14-hydroxyaflavinine (8), two sterically congested indole diterpenoids, were accomplished. AlI 3 -promoted alkyne Prins cyclization was exploited to construct their key structural motifs. An electrocyclization-aromatization sequence assembled the pentasubstituted arene of 6, and a Stille-Migita coupling furnished the tetrasubstituted olefin of 8. The benzylic and allylic C-O bonds were reductively cleaved at the late stage of the syntheses, respectively.

The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a propiolate, (ii) intramolecular Friedel-Crafts acylation, and (iii) site-selective cleavage of an aryl methyl ether.

To develop potent chemotherapeutic agents for treating colorectal cancers, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamide derivatives were designed. Twenty-two novel derivatives were synthesized and their cytotoxicities were measured using a clonogenic long-term survival assay. Of these derivatives, 3-(1-hydroxynaphthalen-2-yl)-N-(3-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazoline-1-carbothioamide (NPC 15) exhibited the best half-maximal cell growth inhibitory concentrations (196.35nM). To explain its cytotoxicity, further biological experiments were performed. Treatment with NPC 15 inhibited cell cycle progression and triggered apoptosis through the caspase-mediated pathway. Its inhibitory effects on several kinases participating in the cell cycle were investigated using an in vitro kinase assay. Its half-maximal inhibitory concentrations for aurora kinases A and B were 105.03μM and 8.53μM, respectively. Further analysis showed that NPC 15 decreased phosphorylation of aurora kinases A, B, and C and phosphorylation of histone H3, a substrate of aurora kinases A and B. Its molecular binding mode for aurora kinase B was elucidated using in silico docking. In summary, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides could be potent chemotherapeutic agents., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their nineteen positional isomers N-(alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides were prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. kansasii and M. smegmatis. Screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. Some of the tested compounds showed antimycobacterial activity comparable with or higher than that of rifampicin. For example, 2-hydroxy-N-(4-propoxyphenyl)-naphthalene-1-carboxamide showed the highest activity (MIC = 12 µM) against M. tuberculosis with insignificant cytotoxicity. N-[3-(But-2-yloxy)phenyl]- and N-[4-(but-2-yloxy)phenyl]-2-hydroxy-naphthalene-1-carboxamide demonstrated high activity against all tested mycobacterial strains and insignificant cytotoxicity. N-(Alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides demonstrated rather high effect against M. smegmatis and M. kansasii and strong antiproliferative effect against the human THP-1 cell line. Lipophilicity was found as the main physicochemical parameter influencing the activity. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Structure-activity relationships are discussed.

The first regio- and stereoselective total synthesis of the axially chiral 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (1) and ancistrotectorine (2) has been described. Both possess a 7,3'-coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis-array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the "lactone method": the two molecular halves, which were activated in an "inverse-halogenated" form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation., Competing Interests: Please note that DJT has the following conflict of interest: Baylor College of Medicine, with DJT as primary inventor, filed composition and methods of use patents on C188 and C188-9. StemMed, Ltd. currently holds an exclusive license to these compounds. DJT is founding partner, President, and CEO of StemMed and also have majority ownership of StemMed. He has been in compliance with all conflict of interests (COI) policies at Baylor College of Medicine and currently is in compliance with all COI policies at StemMed and at the University of Texas M.D. Anderson Cancer Center, where he relocated on December 1, 2014.

Naphthofuran compounds have been known to regulate HNF 4α which is associated with proliferation, progression and metastasis of HCC. In this study, we investigated whether N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-carboxamide (NHDC), a novel synthetic naphthofuran compound inhibits liver tumor growth through activation of HNF 4α. Treatment with different concentrations (1-10.8 µM) of NHDC for various periods (0-72 h) inhibited liver cancer cells (HepG2, Hep3B) growth as well as colony formation followed by induction of apoptosis in a concentration dependent manner. NHDC also induced expression of the apoptosis regulating genes as well as inhibiting the action of STAT3. These inhibitory effects were associated with enhancement of expression and DNA binding activity of HNF 4α. In vivo study confirmed that liver tumor growth was prevented with NHDC (5 mg/kg), and its effect was also related with inhibition of STAT3 pathway through enhancement of expression and DNA binding activity of HNF 4α. Moreover, siRNA of HNF 4α abolished NHDC-induced cell growth inhibition as well as DNA binding activity and phosphorylation of STAT3. Pull down assay docking prediction analysis proved that NHDC directly binds to hydrophobic fatty acid ligand binding site of HNF 4α. A novel naphthofuran compound, NHDC inhibited liver tumor growth by inactivating of STAT3 through direct biding to HNF 4α., (© 2015 Wiley Periodicals, Inc.)

An efficient asymmetric synthesis of 11-β-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.

Automated production of a promising radiopharmaceutical (-)-(1-(8-(2-[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([(18)F]VAT) for the vesicular acetylcholine transporter(VAChT) was achieved using a two-step procedure in a current Good Manufacturing Practices fashion. The production of [(18)F]VAT was accomplished in approximately 140 min, with radiochemical yield of ~15.0% (decay corrected), specific activity>111 GBq/µmol, radiochemical purity>99% and mass of VAT ~3.4 μg/batch (n>10). The radiopharmaceutical product meets all quality control criteria for human use, and is suitable for clinical PET studies of VAChT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Accurate real-time measurements of the dynamics of proton concentration gradients are crucial for detailed molecular studies of proton translocation by membrane-bound enzymes. To reduce complexity, these measurements are often carried out with purified, reconstituted enzyme systems. Yet the most paramount problem to detect pH changes in reconstituted systems is that soluble pH reporters leak out of the vesicle system during the reconstitution procedure. This requires loading of substantial amounts of pH-sensors into the lumen of unilamellar liposomes during reconstitution. Here, we report the synthesis and detailed characterisation of two lipid-linked pH sensors employing amine-reactive forms of seminaphthorhodafluors (SNARF®-1 dye) and rhodamine probes (pHrodo™ Red dye). Lipid-conjugation of both dyes allowed for efficient detergent-based reconstitution of these pH indicators into liposomes. Vesicle-embedded pHrodo™ displayed excellent photostability and an optimal pH-response between 4 and 7. The suitability of the lipid-linked pHrodo™ probe as a pH reporter was demonstrated by assaying the activity of a plant plasma membrane H(+)-ATPase (proton pump) reconstituted in proteoliposomes.

A novel and efficient strategy for the synthesis of sterically hindered 4-amino-3-acyl-2-naphthols through a palladium-catalyzed coupling reaction involving isocyanide chemselective insertion and domino isomerization has been developed. The methodology, which is in accordance with the principle of "atom and step economy", efficiently constructs 4-amino-3-acyl-2-naphthols in moderate to good yields.

Dinaphthothiophene has been reported as a promising p-type semiconductor. The development of high-performance n-type semiconductors is highly desirable. The introduction of an imide group into polycyclic aromatic hydrocarbons can lower their LUMO levels to meet the basic requirement of n-type organic semiconductor materials. In this work, we have synthesized four imide-modified dinaphthothiophenes and dinaphthothiophenedioxides. Their optoelectronic properties have been investigated. Their low-lying LUMO levels make them potential n-type semiconductor candidates.

Synthesis and characterization of a series of new amino-phenol/naphthol ligands (L(1,2)-H) have been developed and their respective zinc complexes ( 1 and 2-Zn ) have been synthesized. The molecular structures of L(1)-H and 1, 2-Zn were explored in detail by NMR, single-crystal X-ray studies and DFT calculations, which confirmed the existence of complexes as stabile dimers both in a solution and in the solid state. All complexes mediate the ring-opening polymerization (ROP) of lactide highly efficiently, at room temperature, in a controlled fashion. The influence of the architecture of the ligand on the desired homo/heteroleptic complex formation, as well as the relationship between the initiator design and the catalytic activity have been investigated.

A novel route has been developed for regioselective synthesis of highly substituted α-naphthols, binaphthols, and anthracenol through silver(I) catalyzed C(sp(3))-H/C(sp)-H, C(sp(2))-H/C(sp)-H functionalization of β-ketoesters and alkynes, respectively, in a single step using water as a solvent. This protocol exhibited broad substrate scope and paved the way for synthesis of anticancer arylnaphthalene lignan natural products such as diphyllin, taiwanin E, and justicidin A with excellent selectivity.

A new naphthol-appended calix[4]arene (NOC4) has been synthesized and characterized. NOC4 is clicked onto a microstructured Au surface and exhibits selective macroscopic recognition of metolcarb (MC) via contact angle measurements. The proposed wettability sensing device displays remarkable specificity and is fast and easy to use, which should be suitable for the rapid detection of MC in environmental monitoring.

A 2H-naphtho[1,2-b]pyran, prepared by dimerization of 2-bromo-3-methyl-1,4-naphthoquinone and O-methylation, readily undergoes solid-state [2 + 2] photodimerization to give a photodimer in excellent yield and with excellent selectivity. Retro [2 + 2] cycloaddition can be achieved by irradiation of a solution of the photodimer in chloroform. Interestingly, the 2H-naphtho[1,2-b]pyran dimerizes with a skeletal rearrangement to afford 2,5-dihydro-1-benzoxepin dimers upon irradiation in methanol or via irradiation with hexamethylditin. Furthermore, treatment of the resulting dimers with triethylamine regenerates the 2H-naphtho[1,2-b]pyran monomer. Significant differences in the color, fluorescence, and cytotoxic properties of the monomer and dimers were observed.