- 4,6-Diphenylpyridines as Promising Novel Anti-Influenza Agents Targeting the PA-PB1 Protein-Protein Interaction: Structure-Activity Relationships Exploration with the Aid of Molecular Modeling
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Influenza is an infectious disease that represents an important public health burden, with high impact on the global morbidity, mortality, and economy. The poor protection and the need of annual updating of the anti-influenza vaccine, added to the rapid emergence of viral strains resistant to current therapy make the need for antiviral drugs with novel mechanisms of action compelling. In this regard, the viral RNA polymerase is an attractive target that allows the design of selective compounds with reduced risk of resistance. In previous studies we showed that the inhibition of the polymerase acidic protein-basic protein 1 (PA-PB1) interaction is a promising strategy for the development of anti-influenza agents. Starting from the previously identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified this scaffold and explored its structure-activity relationships. Noncytotoxic compounds with both the ability of disrupting the PA-PB1 interaction and antiviral activity were identified, and their mechanism of target binding was clarified with molecular modeling simulations.
- Trist, Iuni M. L.,Nannetti, Giulio,Tintori, Cristina,Fallacara, Anna Lucia,Deodato, Davide,Mercorelli, Beatrice,Palù, Giorgio,Wijtmans, Maikel,Gospodova, Tzveta,Edink, Ewald,Verheij, Mark,De Esch, Iwan,Viteva, Lilia,Loregian, Arianna,Botta, Maurizio
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- Substitution of β-nitrostyrenes by electrophilic carbon-centered radicals
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Various trans-β-alkylstyrenes (55-90% yield) were isolated from the free radical addition/elimination process of α-iodocarboxylic acid derivatives with β-nitrostyrenes using dilauroyl peroxide as initiator. The corresponding xanthates give low yields of the alkene under similar conditions.
- García-Torres, Alejandro,Cruz-Almanza, Rymundo,Miranda, Luis D.
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- Diphenylmorpholine CMPO: Synthesis, coordination behavior and extraction studies of actinides
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Carbamoylmethyl phosphine oxide (CMPO) derivatives are well known ligands in the separation and extraction of trivalent lanthanides and actinides from nuclear waste. The substituents of CMPO play major role in their selectivity and extractability. We report the synthesis and characterization of diphenylmorpholine carbamoylmethyl phosphine oxide (DPMCMPO) (L1) and diphenyl-N,N-diethyl carbamoylmethyl phosphine oxide (DPDECMPO) (L2) using various spectroscopic techniques, such as FT-IR, 1H, 13C, and 31P NMR. The molecular structure of DPMCMPO is confirmed by single crystal XRD analysis. The present study aims to understand the influence of substituents on ‘N’ atom of L1 (morpholine based DPMCMPO) and L2 (diethyl substituted DPDECMPO) ligands for the extraction of some selected actinide ions such as Th(IV), U(VI) and Am(III). The geometry and electronic structure of these ligands and their respective complexes with Th(NO3)4 and UO2(NO3)2 are further explored using density functional theory (DFT) calculations. The employed ligands (L1 and L2) show greater distribution values for Th(IV) over U(VI), due to strong “ligand-Th” complexation ability as suggested by DFT calculations.
- Das, Dhrubajyoti,Sivaramakrishna, Akella,Gopakumar, Gopinadhanpillai,Brahmmananda Rao,Sivaraman,Vijayakrishna, Kari
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- A novel benzothiazole derivative SKLB826 inhibits human hepatocellular carcinoma growth via inducing G2/M phase arrest and apoptosis
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Hepatocellular carcinoma is the fifth most common cancer and durable responses in conventional treatments are limited so researchers have been devoted to developing new anti-HCC agents. Benzothiazole derivatives are known for various biological activities and have received considerable attention in cancer therapy, hence we designed and synthesized a novel potent benzothiazole compound 2-chloro-N-(2-(2-(2-morpholino-2-oxoethyl)thio)-2,3-dihydrobenzo[d]thiazol-6-yl)acetamide (SKLB826) and further investigated the biological activities against cancer. The results suggested that SKLB826 showed growth inhibition against a broad spectrum of human cancer cells, especially human HCC cell lines, in a dose-dependent manner and induced G2/M phase arrest via down-regulating the CDK1, cyclinA2 and cdc25c protein levels. SKLB826 could also induce apoptosis of HCC cells via decreasing the expression of Bcl-2 and increasing the levels of BAX and cleaved caspase-3, 9. Moreover, after treatment with SKLB826, the change of ROS level and ΔΨm suggested that SKLB826 might induce apoptosis through an intrinsic mitochondrial apoptotic pathway. Furthermore, SKLB826 could suppress tumor growth in the HepG2 xenograft model without inducing any notable major organ-related toxicity, suggesting that SKLB826 may be a potential candidate for HCC therapy.
- Lei, Qian,Zhang, Lidan,Xia, Yong,Ye, Tinghong,Yang, Fangfang,Zhu, Yongxia,Song, Xuejiao,Wang, Ningyu,Xu, Ying,Liu, Xiaowei,Yu, Luoting
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- Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors
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Abstract A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.
- Brullo, Chiara,Massa, Matteo,Villa, Carla,Ricciarelli, Roberta,Rivera, Daniela,Pronzato, Maria Adelaide,Fedele, Ernesto,Barocelli, Elisabetta,Bertoni, Simona,Flammini, Lisa,Bruno, Olga
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- TRICHLOROETHYLENE IN ORGANIC SYNTHESIS: II. REACTION OF TRICHLOROETHYLENE WITH SECONDARY AMINES
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In a novel reaction, trichloroethylene reacts with secondary aliphatic amines in the presence of aqueous solution of NaOH and catalytic quantity of benzyltriethylammonium chloride to give the corresponding N,N,N',N'-tetraalkylsubstituted glycinamides.The following glycinamides were obtained with high yield: (N-morpholine)acetic acid morpholide, N-(piperidineacetyl)piperidine, N,N,N',N'-tetra-n-butylglycinamide and N,N,N',N'-tetraethylglycinamide.Mechanism of the reaction is discussed.
- Pielichowski, Jan,Popielarz, Roman
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- Synthesis, in vitro skin permeation studies, and PLS-analysis of new naproxen derivatives
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Purpose. To synthesize new naproxen (01) derivatives with amide or ester structures or with a combination of the two (02-15). To compare their physicochemical properties with naproxen esters (16-22) and their respective skin permeation behavior. To study structure-permeation relationships via partial least squares (PLS)-analysis. Methods. Stability, aqueous, and octanol solubility were determined. Lipophilicity and further 53 chemical descriptors were computed. A suitable in-vitro skin permeation model was developed to compare maximal flux (Jmax) of derivatives. Based on these flux data, PLS-analysis was performed to derive structure-permeation relationships. Results. None of the new derivatives showed an improved flux in comparison to naproxen. This result can be explained by PLS-analysis: skin permeation increases with the solubility both in water and in octanol. For a good permeation, an optimized molecule should exhibit a small volume with a spherical shape. The surface area should be large in relation to volume, as indicated by the rugosity parameter. A clear separation between the hydrophobic and the hydrophilic domain (= high amphiphilic moment) is favorable. Lipophilicity is inversely correlated with skin permeation. Conclusions. PLS-analysis is a valuable tool to derive significant, internally predictive quantitative models for structure-permeation relationships of naproxen derivatives in the above described skin permeation assay.
- Weber,Steimer,Mannhold,Cruciani
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- Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer
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1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.
- Alotaibi, Faez,Halaweish, Fathi,Halaweish, Hossam,Iram, Surtaj,Kasten, Abigail,Kyeremateng, Jennifer,Ostlund, Trevor
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- De novo Design of SARS-CoV-2 Main Protease Inhibitors
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The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, M Pro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar noncovalent inhibitors of the viral main protease.
- Dovala, Dustin,Fischer, Christian,Nomura, Daniel K.,Peitsinis, Zisis,Spradlin, Jessica N.,Trauner, Dirk,Yang, Chao,Zhang, Yingkai,Rühmann, Klaus-Peter,Vep?ek, Nynke A.
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supporting information
(2021/10/16)
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- Microwave-assisted synthesis, structural characterization and assessment of the antibacterial activity of some new aminopyridine, pyrrolidine, piperidine and morpholine acetamides
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A series of new acetamide derivatives 22–28 of primary and secondary amines and para-toluene sulphinate sodium salt have been synthesized under microwave irradiation and assessed in vitro for their antibacterial activity against one Gram-positive and two Gram-negative bacterial species such as S. pyogenes, E. coli, and P. mirabilis using the Mueller-Hinton Agar diffusion (well diffusion) method. The synthesized compounds with significant differences in inhibition diameters and MICs were compared with those of amoxicillin, ampicillin, cephalothin, azithromycin and doxycycline. All of the evaluated acetamide derivatives were used with varying inhibition concentrations of 6.25, 12.5, 37.5, 62.5, 87.5, 112.5 and 125 μg/mL. The results show that the most important antibacterial properties were displayed by the synthetic compounds 22 and 24, both of bear a para-chlorophenyl moiety incorporated into the 2-position moiety of acetamide 1. The molecular structures of the new compounds were determined using the FT-IR and1H-NMR techniques.
- Abdulghani, Saba S.,Alsamarrai, Abdulmajeed S. H.
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- Synthesis and in vitro antileishmanial efficacy of novel quinazolinone derivatives
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Currently available drugs being used to treat leishmaniasis have several shortcomings, including high toxicity, drug administration that requires hospitalization, and the emergence of parasite resistance against clinically used drugs. As a result, there is a dire need for the development of new antileishmanial drugs that are safe, affordable, and efficient. In this study, two new series of synthesized quinazolinone derivatives were investigated as potential future antileishmanial agents, by assessing their activities against the Leishmania (L.) donovani and L.?major species. The cytotoxicity profiles of these derivatives were assessed in vitro on Vero cells. The compounds were found to be safer and without any toxic activities against mammalian cells, compared to the reference drug, halofuginone, a clinical derivative of febrifugine. However, they had demonstrated poor antileishmanial growth inhibition efficacies. The two compounds that had been found the most active were the mono quinazolinone 2d and the bisquinazolinone 5b with growth inhibitory efficacies of 35% and 29% for the L.?major and L.?donovani 9515 promastigotes, respectively. These outcomes had suggested structural redesign, inter alia the inclusion of polar groups on the quinazolinone ring, to potentially generate novel quinazolinone derivatives, endowed with effective antileishmanial potential.
- Prinsloo, Izak F.,Zuma, Nonkululeko H.,Aucamp, Janine,N’Da, David D.
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p. 383 - 398
(2020/09/23)
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- Naproxen based 1,3,4-oxadiazole derivatives as EGFR inhibitors: Design, synthesis, anticancer, and computational studies
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A library of novel naproxen based 1,3,4-oxadiazole derivatives (8–16 and 19–26) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hy-brids, compound2-(4-((5-((S)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol(15) was the most potent compound against MCF-7 and HepG2cancer cells with IC50 of 2.13 and 1.63 μg/mL, respectively, and was equipotent to doxorubicin (IC50 1.62 μg/mL) towards HepG2. Furthermore, compound 15 inhibited EGFR kinase with IC50 0.41 μM compared to standard drug Erlotinib (IC50 0.30 μM). The active compound induces a high percentage of necrosis towards MCF-7, HePG2 and HCT 116 cells. The docking studies, DFT and MEP also supported the biological data. These results demonstrated that these synthesized naproxen hybrids have EGFR inhibition effects and can be used as leads for cancer therapy.
- Alam, Mohammad Mahboob,Alfaifi, Mohammad Y.,Alfaifi, Sulaiman Y. M.,Almalki, Abdulraheem S. A.,Alsenani, Nawaf I.,Alsharif, Meshari A.,Elbehairi, Serag Eldin I.,Elhenawy, Ahmed A.,Malebari, Azizah M.,Nazreen, Syed
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- Synthesis of arylfuran derivatives as potential antibacterial agents
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Bacterial infections represent a serious health care problem mainly due to the misuse and overuse of antibiotics, with consequent emergence of multidrug resistant bacterial strains. Then, because the urgent need to find novel and alternative antibacterial agents, the present work focuses on the synthesis of arylfuran derivatives with potential antimicrobial activity. Eighteen arylfuran derivatives were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Among them, seven compounds containing an amino group in their structure showed activity, with compound 24 being the most effective against both Gram-negative (E. coli, MIC = 49 μM) and Gram-positive (S. aureus, MIC = 98 μM) bacteria, besides having exhibited a modest activity against P. aeruginosa (MIC = 770 μM). In addition, based on in silico studies, this is a druglike compound since it does not violate any rules for predicting oral bioavailability. In this context, the significant antibacterial potential and the low similarity with known antibiotics indicate the innovative aspect of compound 24.
- Andrade, Marina M. S.,Protti, ícaro F.,Maltarollo, Vinícius G.,da Costa, Ygor F. G.,de Moraes, Wesley G.,Moreira, Nicole F.,Garcia, Giovana G.,Caran, Gabriel F.,Ottoni, Flaviano M.,Alves, Ricardo J.,Moreira, Carolina P. S.,Martins, Helen R.,Alves, Maria Silvana,de Oliveira, Renata B.
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p. 1074 - 1086
(2021/02/26)
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- Quinazoline derivative and application thereof as antitumor drug
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The invention belongs to the technical field of medicinal chemistry, and relates to a quinazoline derivative shown as a general formula (I), physiologically acceptable salt formed by the quinazoline derivative and inorganic or organic acid, a pharmaceutical composition containing the quinazoline derivative and the physiologically acceptable salt, and application of the quinazoline derivative and the pharmaceutical composition to preparation of drugs for treating tumor diseases, particularly drugs for treating abnormal EGFR family diseases. The compound has pharmacological properties with important values, and especially has an inhibition effect on signal transduction caused by tyrosine kinase.
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Paragraph 0040; 0042-0044; 0047
(2020/08/22)
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- Design and synthesis of some barbituric and 1,3-dimethylbarbituric acid derivatives: A non-classical scaffold for potential PARP1 inhibitors
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Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50 = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC50 = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50 = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.
- Eldin A. Osman, Essam,Hanafy, Noura S.,George, Riham F.,El-Moghazy, Samir M.
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- Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents
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A total of 26 compounds based on osthole skeleton were designed, synthesized. Their cytoprotective abilities of antioxidation, anti-inflammation and Aβ42(Amyloid β-protein 42)-induced neurotoxicity were evaluated by MTT assays. Mechanism of the action of selected compounds were investigated by molecular docking. AlogP, logS and blood–brain barrier (BBB) permeability of all these compounds were simulated by admetSAR. Most of the compounds showed better antioxidative and anti-inflammatory activities compared with osthole, especially OST7 and OST17. The compound OST7 showed relative high activity in neuroprotection against H2O2 (45.7 ± 5.5%), oxygen glucose deprivation (64.6 ± 4.8%) and Aβ42 (61.4 ± 5.2%) at a low concentration of 10 μM. EC50 of selected compounds were measured in both H2O2 and OGD induced cytotoxicity models. Moreover, NO inhibiting ability of OST17(50.4 ± 7.1%) already surpassed the positive drug indomethacin. The structure activity relationship study indicated that introduction of piperazine group, tetrahydropyrrole group and aromatic amine group might be beneficial for enhancement of osthole neuroprotective properties. Molecular docking explained that the reason OST7 exhibited relatively stronger neuroprotection against Aβ because of the greater area of interactions between molecule and target protein. OST7 and OST17 both provided novel methods to investigate osthole as anti-AD drugs.
- Zhang, Li,Wu, Yuhang,Yang, Guixiang,Gan, Haixian,Sang, Dayong,Zhou, Jiye,Su, Lin,Wang, Rui,Ma, Lei
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supporting information
(2020/11/03)
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- COVALENT TARGETING OF E3 LIGASES
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Disclosed herein, inter alia, are compositions and methods for targeting E3 ligases. In an aspect is a targeted protein degrader including 1) a targeted protein binder and 2) an E3 Ubiquitin ligase binder, wherein the E3 Ubiquitin ligase is human RNF4 or human RNF114. In an aspect is provided a pharmaceutical composition including a compound as described herein, including embodiments, and a pharmaceutically acceptable excipient.
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Paragraph 0591-0592; 0626; 0631
(2020/05/19)
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- Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells
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Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
- Roberti, Marinella,Schipani, Fabrizio,Bagnolini, Greta,Milano, Domenico,Giacomini, Elisa,Falchi, Federico,Balboni, Andrea,Manerba, Marcella,Farabegoli, Fulvia,De Franco, Francesca,Robertson, Janet,Minucci, Saverio,Pallavicini, Isabella,Di Stefano, Giuseppina,Girotto, Stefania,Pellicciari, Roberto,Cavalli, Andrea
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- Phenylacetic acid ester compound and use thereof
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The invention relates to a phenylacetate compound as shown in a general formula (I) and a pharmaceutical composition containing the phenylacetate compound, as well as application in anesthesia and sedation.
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Paragraph 0059; 0069-0071
(2019/03/02)
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- A quinazoline derivative and its preparation method and application (by machine translation)
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The invention discloses a 4 - (4 '- substituted phenyl) amino - 6, 7 - dimethoxy quinazoline derivatives; the quinazoline derivatives of the formula II synthesis method for compound 4 - (4' - hydroxy phenyl) amino - 6, 7 - dimethoxy quinazoline, type III compounds and alkaline reagent to dissolve in the solvent, stirring at room temperature the reaction 15h - 24h; after the reaction cooling and filtering to obtain the crude product, obtained after the refining of crude yellow solid powder; quinazoline derivatives of the present invention human cervical carcinoma cells, human liver cancer cells, human lung cancer cells, human breast cancer cells with human colon cancer cells has better inhibition activity, can be used as a lead compound in the treatment of cancer, its preparation method is simple and feasible, is easy to operate. (by machine translation)
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Paragraph 0100-0103
(2019/02/26)
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- Synthesis, Antimicrobial Evaluation, and Docking Studies of Substituted Acetylphenoxymethyl-triazolyl-N-phenylacetamides
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A series of molecules containing acetylphenoxymethyl, triazole, and N-phenylacetamide moieties were synthesized via the click chemistry approach. All the synthesized compounds were screened for their antimicrobial activities in vitro. The synthesized compounds 8a, 8b, 8m, and 8n showed better activities. We further performed exploratory docking studies to gain some insight regarding the molecular mechanism of antibacterial action of these compounds that could guide further structure-activity relationship (SAR) studies. We examined the interaction of the most active compound with DNA gyrase (pdb id:1KZN). Based on antimicrobial and docking studies, the compounds 8a, 8b, 8m, and 8n were identified as potential antimicrobial agents.
- Phatak, Pramod S.,Sathe, Bhaurao P.,Dhumal, Sambhaji T.,Rehman, Naziya N. M. A.,Dixit, Prashant P.,Khedkar, Vijay M.,Haval, Kishan P.
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- Betulinic acid derivatives: a new class of α-glucosidase inhibitors and LPS-stimulated nitric oxide production inhibition on mouse macrophage RAW 264.7 cells
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Chemical manipulation studies were conducted on betulinic acid (1), twenty-one new rationally designed analogues of 1 with modifications at C-28 were synthesized for their evaluation of inhibitory effects on α-glucosidase and LPS-stimulated nitric oxide production in mouse macrophage RAW 264.7 cells. Compound 2 (IC50 = 5.4 μM) exhibited an almost 1.4-fold increase in α-glucosidase inhibitory activity on yeast α-glucosidase while analogues 5 (IC50 16.4 μM) and 11 (IC50 16.6 μM) exhibited a 2-fold enhanced inhibitory activity on NO-production than betulinic acid.
- Gundoju, Narayanarao,Bokam, Ramesh,Yalavarthi, Nageswara Rao,Azad, Rajaram,Ponnapalli, Mangala Gowri
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p. 2618 - 2622
(2018/04/30)
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- Design and Synthesis of New Aryloxy-linked Dimeric 1,2,3-Triazoles via Click Chemistry Approach: Biological Evaluation and Molecular Docking Study
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A quest for more potent new antitubercular agents has prompted to design and synthesize aryloxy-linked dimeric 1,2,3-triazoles (4a–j), from azides (2a-e) and bis(prop-2-yn-1-yloxy)benzene (3a–b) on 1,3-dipolar cycloaddition reaction via copper (I)-catalyzed click chemistry approach with good to better yields. The titled compounds (4a–j) were designed using molecular hybridization approach by assembling various bioactive pharmacophoric fragments in a single molecular framework. All the synthesized compounds have been screened for their in vitro antitubercular, antifungal, and antioxidant activities against their respective strains. Among them, 4h and 4i show the highest antifungal activity, whereas compounds 4h, 4i, and 4j have revealed promising antitubercular activity against their respective strains. In addition to this, most of the synthesized compounds were found as potent antifungal and antioxidant agents. A significant network of bonded and non-bonded interactions stabilized these molecules into the active site of fungal CYP51 that is realized from the obtained well-placed docking poses and the associated thermodynamic interactions with the enzyme. The synthesized compounds have also been analyzed for absorption, distribution, metabolism, and excretion properties.
- Deshmukh, Tejshri R.,Khare, Smita P.,Krishna, Vagolu S.,Sriram, Dharmarajan,Sangshetti, Jaiprakash N.,Bhusnure, Omprakash,Khedkar, Vijay M.,Shingate, Bapurao B.
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p. 2144 - 2162
(2019/07/12)
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- Substituted Aminoacetamides as Novel Leads for Malaria Treatment
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Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.
- Norcross, Neil R.,Wilson, Caroline,Baraga?a, Beatriz,Hallyburton, Irene,Osuna-Cabello, Maria,Norval, Suzanne,Riley, Jennifer,Fletcher, Daniel,Sinden, Robert,Delves, Michael,Ruecker, Andrea,Duffy, Sandra,Meister, Stephan,Antonova-Koch, Yevgeniya,Crespo, Benigno,de Cózar, Cristina,Sanz, Laura M.,Gamo, Francisco Javier,Avery, Vicky M.,Frearson, Julie A.,Gray, David W.,Fairlamb, Alan H.,Winzeler, Elizabeth A.,Waterson, David,Campbell, Simon F.,Willis, Paul A.,Read, Kevin D.,Gilbert, Ian H.
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supporting information
p. 1329 - 1335
(2019/07/17)
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- Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries
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Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.
- Jing, Lanlan,Wu, Gaochan,Hao, Xia,Olotu, Fisayo A.,Kang, Dongwei,Chen, Chin Ho,Lee, Kuo-Hsiung,Soliman, Mahmoud E.S.,Liu, Xinyong,Song, Yuning,Zhan, Peng
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- A synthesis method of pinaverium bromide
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The invention relates to a pinaverium bromide synthesis method. Cheap and easily available morpholine as a raw material and an acylating agent undergo a reaction to produce a novel intermediate and pinaverium bromide is synthesized from the intermediate under mild conditions. Raw material reaction is complete, side reaction is less, the pinaverium bromide has treatment cis-isomeride content greater than or equal to 99% and trans-isomer content less than or equal to 1%, and product cis-isomer content is greatly improved.
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Paragraph 0043-0045; 0061-0063; 0071-0073
(2018/11/04)
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- Synthesis and in vitro cytotoxicity evaluation of β-carboline-linked 2,4-thiazolidinedione hybrids: potential DNA intercalation and apoptosis-inducing studies
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A series of new β-carboline-thiazolidinedione hybrids was synthesized and assessed for in vitro cytotoxicity potential against selected human cancer cell lines, namely, PC-3, A549, MG-63, HCT-15, MDA-MB-231, A431, and PANC-1 along with a normal human cell line (L-132). Among this new series, compound 19e was found to exhibit promising cytotoxic effects against triple negative breast cancer cell line (MDA-MB-231) with IC50 value of 0.97 ± 0.13 μM. Hence, further mechanistic studies of the apoptosis-inducing effect of 19e were conducted on the MDA-MB-23 cell line. Moreover, characteristic apoptotic features such as membrane blebbing, chromatin condensation, and apoptotic body formation were observed with the effect of 19e on MDA-MB-231 cells using AO/EB and DAPI staining. The Annexin V-Alexa Flour 488/PI assay confirmed significant early apoptosis induction. Notably, DCFDA assay indicated that 19e induced ROS generation. Moreover, mitochondrial membrane potential collapse was observed through JC-1 staining by 19e. Furthermore, cell cycle analysis revealed that 19e arrested cells in the sub G1 phase. In addition, clonogenic and wound healing assays indicated inhibition of colony formation and cell migration by 19e in a dose-dependent manner. Next, molecular modelling and DNA binding affinity studies such as relative viscosity, circular dichroism and UV-visible spectroscopy denoted classic intercalation of 19e with CT-DNA with binding constant of 1 × 105 M?1.
- Tokala, Ramya,Thatikonda, Sowjanya,Sana, Sravani,Regur, Phanindranath,Godugu, Chandraiah,Shankaraiah, Nagula
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p. 16226 - 16236
(2018/10/04)
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- New thiazolidine-2,4-dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity
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Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine-2,4-dione framework (TZD-4) prompted us to explore compounds containing both the thiazolidine-2,4-dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene-based thiazolidine-2,4-dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine-resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD-4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD-4 against the P. falciparum parasite. All the synthesised compounds were non-toxic and often showed >90% viability of the HeLa cell line screened.
- Oderinlo, Ogunyemi O.,Tukulula, Matshawandile,Isaacs, Michelle,Hoppe, Heinrich C.,Taylor, Dale,Smith, Vincent J.,Khanye, Setshaba D.
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-
- Compound and application of compound to treating colon cancer
-
The invention discloses a compound and application of the compound to treating the colon cancer. The structural formula of the compound is shown in the formula I, wherein R1, R2, R3 and R4 in the formula I are respectively independently chosen from alkyl groups and alkoxy groups, the number of hydrogen atoms, halogen, nitro and carbon atoms in the alkyl group is 1-6, the number of carbon atoms in the alkoxy group is 1-6, R5 is chosen from nitro and -NR6R7, wherein R6 and R7 are respectively independently the hydrogen atom or CH2Ar, the Ar represents a phenyl group or an aryl group, the para-position of the aryl group is substituted by R8, the aryl group is a phenyl group, the R8 is an alkoxy group or the following shown groups, and the number of halogen, hydroxyl and carbon atoms in the R8 is 1-6. The compound also has an obvious effect on inhibiting a tumor sphere from a cancer patient with the colon cancer. In addition, the compound also has an obvious effect on inhibiting the migration and the moving ability of a colon cancer cell line. A novel medicine for treating the colon cancer is expected to be developed on the basis of the compound.
- -
-
Paragraph 0191-0193
(2017/11/04)
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- Conventional and microwave-assisted synthesis of new 1H-benzimidazole-thiazolidinedione derivatives: A potential anticancer scaffold
-
A series of new benzimidazole bearing thiazolidinedione derivatives has been designed, synthesized by using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the derivatives. All the new synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines of breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and bone (HT1080) along with a normal kidney cells (HeK-293T). The compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50 values in the range of 0.096–0.63 μM on PC-3, HeLa, A549 and HT1080 cancer cells. Most of the compounds have found to be safe on normal HeK-293T kidney cells in comparison to cancer cells. The treatment of cells with 17p and 17q showed the typical apoptotic morphological features like fragmentation and shrinkage of nuclei. Further, test compounds resulted in inhibition of cell migration through disruption of F-actin protein assembly. Hoechst, DCFH-DA staining, mitochondrial membrane and annexin binding assays revealed that the cancer cell proliferation was inhibited through induction of apoptosis in A549 cells.
- Sharma, Pankaj,Reddy, T. Srinivasa,Kumar, Niggula Praveen,Senwar, Kishna Ram,Bhargava, Suresh K.,Shankaraiah, Nagula
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p. 234 - 245
(2017/07/04)
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- Triazole derivative having HSP90 (Heat Shock Protein) inhibiting activity, as well as preparation method and application of triazole derivative
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The invention discloses a triazole derivative having an HSP90 (Heat Shock Protein) inhibiting activity, as well as a preparation method and an application of the triazole derivative. Specifically, the invention relates to the triazole derivative having a structure as shown in a formula (I), a stereisomer of the triazole derivative and a pharmaceutically acceptable salt, wherein the definition of each substituent group in the formula (I) and the definition in a description are the same. The compound with a novel structure has the HSP90 inhibiting activity, can be used to cure cancers, neurodegenerative disorders, inflammation diseases, autoimmune diseases, ischemic brain injuries and the like, and has a broad application prospect.
- -
-
Paragraph 0342; 0343; 0344
(2017/08/02)
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- Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors
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Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.
- Joncour, Agnès,Desroy, Nicolas,Housseman, Christopher,Bock, Xavier,Bienvenu, Natacha,Cherel, La?titia,Labeguere, Virginie,Peixoto, Christophe,Annoot, Denis,Lepissier, Luce,Heiermann, J?rg,Hengeveld, Willem Jan,Pilzak, Gregor,Monjardet, Alain,Wakselman, Emanuelle,Roncoroni, Veronique,Le Tallec, Sandrine,Galien, René,David, Christelle,Vandervoort, Nele,Christophe, Thierry,Conrath, Katja,Jans, Mia,Wohlkonig, Alexandre,Soror, Sameh,Steyaert, Jan,Touitou, Robert,Fleury, Damien,Vercheval, Lionel,Mollat, Patrick,Triballeau, Nicolas,Van Der Aar, Ellen,Brys, Reginald,Heckmann, Bertrand
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p. 7371 - 7392
(2017/09/23)
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- Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification
-
Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50values ranging from 15 to 125?μM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC50?=?15?μM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC50?=?67.7?μM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC50?=?3.1?μM) with remarkable selectivity index (SI?=?128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.
- Braga, Saulo Fehelberg Pinto,Martins, Luan Carvalho,da Silva, Elany Barbosa,Sales Júnior, Policarpo Ademar,Murta, Silvane Maria Fonseca,Romanha, Alvaro José,Soh, Wai Tuck,Brandstetter, Hans,Ferreira, Rafaela Salgado,de Oliveira, Renata Barbosa
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supporting information
p. 1889 - 1900
(2017/03/08)
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- NOVEL 3-INDOL SUBSTITUTED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE
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A compound of Formula I is provided: or pharmaceutically acceptable enantiomers, salts or solvates thereof. The 5 invention further relates to the use of the compounds of Formula I as TDO2 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity. The invention also 10 relates to a process for manufacturing compounds of Formula I.
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Page/Page column 222
(2016/10/04)
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- GLUCOSE UPTAKE INHIBITORS
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Provided hererin are compounds that modulate glucose uptake activityand are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: Formula (I) wherein the variables have the values disclosed herein.
- -
-
Paragraph 0169-0170
(2017/01/09)
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- Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents
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A series of new (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 μM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΦm) was also affected and the levels of intracellular Ca2+ were raised.
- Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Naidu,Srinivasulu, Gannoju,Shankaraiah, Nagula
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- Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism in Vivo
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Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2O2-induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment. Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. The results of the biological evaluation showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.
- Dong, Ze-Xi,Shi, Zhi-Hao,Li, Nian-Guang,Zhang, Wei,Gu, Ting,Zhang, Peng-Xuan,Wu, Wen-Yu,Tang, Yu-Ping,Fang, Fang,Xue, Xin,Li, He-Min,Cheng, Hai-Bo,Yang, Jian-Ping,Duan, Jin-Ao
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p. 946 - 957
(2016/05/24)
-
- Synthesis and biological evaluation of new benzimidazole-thiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents
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A series of new benzimidazole-thiazolidinedione hybrids has been synthesized and evaluated for their cytotoxic potential against a selected human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A). Among the tested compounds, 11p exhibited promising cytotoxicity with IC50value of 11.46?±?1.46?μM on A549 lung cancer cell line and did not show significant toxicity on normal MCF10A cells. Lung cancer cells (A549) have been used to know the mechanism of cell growth inhibition and apoptosis inducing effect with compound 11p. The treatment of A549?cells with 11p showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow-cytometry analysis revealed the G2/M phase of cell cycle arrest in a dose dependent manner. Preliminary mechanistic studies suggested that the cell migration was inhibited through the disruption of F-actin protein. Acridine orange-ethidium bromide (AO-EB), DAPI, annexin V-FITC/propidium iodide, rhodamine-123 and MitoSOX assays suggested the induction of apoptosis in A549 cells by compound 11p.
- Sharma, Pankaj,Srinivasa Reddy,Thummuri, Dinesh,Senwar, Kishna Ram,Praveen Kumar, Niggula,Naidu,Bhargava, Suresh K.,Shankaraiah, Nagula
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supporting information
p. 608 - 621
(2016/09/14)
-
- Synthesis and anticancer potential of novel xanthone derivatives with 3,6-substituted chains
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In an effort to develop new drug candidates with enhanced anticancer activity, our team synthesized and assessed the cytotoxicity of a series of novel xanthone derivatives with two longer 3,6-disubstituted amine carbonyl methoxy side chains on either benzene ring in selected human cancer cell lines. An MTT assay revealed that a set of compounds with lower IC50values than the positive control, 5-FU, exhibited greater anticancer effects. The most potent derivative (XD8) exhibited anticancer activity in MDA-MB-231, PC-3, A549, AsPC-1, and HCT116 cells lines with IC50values of 8.06, 6.18, 4.59, 4.76, and 6.09?μM, respectively. Cell cycle analysis and apoptosis activation suggested that the mechanism of action of these derivatives includes cell cycle regulation and apoptosis induction.
- Liu, Chaomei,Zhang, Mei,Zhang, Zhenhuan,Zhang, Steven B.,Yang, Shanmin,Zhang, Amy,Yin, Liangjie,Swarts, Steven,Vidyasagar, Sadasivan,Zhang, Lurong,Okunieff, Paul
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p. 4263 - 4271
(2016/08/23)
-
- Efficient syntheses of 1,2,3-triazoloamide derivatives using solid- and solution-phase synthetic approaches
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Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; SN2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively.
- Lee, Doohyun,Kim, Daehun,Lee, Seungyeon,Kim, Taegeum,Kim, Joobin,Kim, Sohee,Liu, Kwang-Hyeon,Lee, Sangkyu,Bae, Jong-Sup,Song, Kyung-Sik,Cho, Chang-Woo,Son, Youn Kyung,Baek, Dong Jae,Lee, Taeho
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p. 19984 - 20013
(2015/12/23)
-
- Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy
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Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (ICinf50/inf values 0.141/4M) and cell-free assays (ICinf50/inf values 0.03 1/4M) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.
- Lill, Andreas P.,R?dl, Carmen B.,Steinhilber, Dieter,Stark, Holger,Hofmann, Bettina
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supporting information
p. 503 - 523
(2014/12/11)
-
- Direct Catalytic Asymmetric Aldol Reaction of an α-Azido Amide
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A direct aldol reaction of an α-azido 7-azaindolinylamide, promoted by a Cu-based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7-azaindolinylamide moiety furnished enantioenriched β-hydroxy-α-azido carboxylic acid derivatives.
- Weidner, Karin,Sun, Zhongdong,Kumagai, Naoya,Shibasaki, Masakatsu
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supporting information
p. 6236 - 6240
(2015/05/20)
-
- A C-3-Selective Direct Alkylation of Coumarins by Using a Microwave-Assisted Xanthate-Based Radical Reaction
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A xanthate-based oxidative radical process for the direct alkylation of the coumarin ring system is presented. In the reaction, a vinylic and unactivated C-H bond of the coumarin system is replaced by an α-acyl functionality under neutral conditions. This reaction has a high reaction site selectivity, which can realize alkylation at the C-3 position. A vinylic and unactivated C-H bond of the coumarin system is replaced by an alkyl functionality trough a xanthate-based radical reaction (DLP = dilauroyl peroxide).
- Miranda, Luis D.,Icelo-ávila, Estefanía,Rentería-G?mez, ángel,Pila, Michell,Marrero, Joaquín G.
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supporting information
p. 4098 - 4101
(2015/06/30)
-
- Synthesis of scutellarein derivatives to increase biological activity and water solubility
-
In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.
- Shi, Zhi-Hao,Li, Nian-Guang,Shi, Qian-Ping,Zhang, Wei,Dong, Ze-Xi,Tang, Yu-Ping,Zhang, Peng-Xuan,Gu, Ting,Wu, Wen-Yu,Fang, Fang,Xin-Xue,Li, He-Min,Yang, Jian-Ping,Duan, Jin-Ao
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p. 6875 - 6884
(2015/11/11)
-
- Facile synthesis and antifungal activity of dithiocarbamate derivatives bearing an amide moiety
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Two series of novel dithiocarbamate derivatives bearing an amide moiety, 3a-i and 4a-i, were synthesized by a facile method, and the structures of the derivatives were confirmed by elemental analysis and 1H-NMR, 13C- -NMR and high-resolution mass spectrometry (HRMS). Their antifungal activity against five phytopathogenic fungi were evaluated, and the results showed that most of the target compounds displayed low antifungal activity in vitro against Gibberella zeae, Cytospora sp., Colletotrichum gloeosporioides, Alternaria solani, and Fusarium solani at a concentration of 100 mg L-1. However, two compounds, 4f and 4g, exhibited significant activity against A. solani and C. gloeosporioides, respectively.
- Li, Yu-Wen,Li, Shu-Tao
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p. 1367 - 1374
(2016/02/18)
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- NEW COMPOUNDS HAVING A SELECTIVE PDE4D INHIBITING ACTIVITY
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Compounds of formula (I), wherein Z = cyclopentyl. cyclopropylmethyl, -CH3; R' = -CH3, CHF2, X= formula (II) (III) (IV) (V) Y = - CO; -C=O(CH2), -CH(OH)-CH2, -CH2-C=O, -CH2-CH2-C=O; -CH2-CH(OH)-CH2, -CH2- CH(OCOR1)-CH2 NR2 = -N(CH2-CH2OH)2, formula (VI) (VII) (VIII) (IX) (X) (XI) R1 = optionally substituted C1-C8 alkyl, optionally substituted aryl; optionally substituted aralkyl, preferably C1-C3 alkyl, more preferably CH3; and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof; these compounds have a PDE4D inhibiting activity and can be used as a medicament for treating dementia, in particular Alzheimer disease, and for improving memory.
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Page/Page column 25
(2015/09/22)
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- Discovery and structure-activity relationship of novel 2,3- dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2 h)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 Inhibitors
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Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
- Patel, Maulik R.,Bhatt, Aaditya,Steffen, Jamin D.,Chergui, Adel,Murai, Junko,Pommier, Yves,Pascal, John M.,Trombetta, Louis D.,Fronczek, Frank R.,Talele, Tanaji T.
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p. 5579 - 5601
(2014/08/05)
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- Synthesis of new hybrid heterocyclic compounds having 1,2,3-triazole and isoxazole via click chemistry
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A simple and highly efficient method for the regioselective synthesis of isoxazolyl-1,4-disubstituted-1,2,3-triazoles 6a-l in good to excellent yields from terminal alkynes having isoxazole scaffold 4a-c and various azides through Cu(I)-catalyzed 1,3-dipolar cycloaddition is described. The reaction proceeds smoothly in 1:1 mixture of t-BuOH and water at RT. The structures of all newly synthesized hybrid heterocycles are established on the basis of spectral data ir, 1H nmr, mass, and elemental analysis.
- Jayaprakash Rao,Srinivas
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p. 1675 - 1678
(2015/01/09)
-
- Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2- oxoethyl) oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors
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A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8. SAR considerations, also confirmed by in silico docking simulations, evidenced that both chain and amino terminal function characterized by higher hydrophilicity are required for a good and selective inhibitor-catalytic pocket interaction.
- Brullo, Chiara,Massa, Matteo,Rocca, Massimo,Rotolo, Chiara,Guariento, Sara,Rivera, Daniela,Ricciarelli, Roberta,Fedele, Ernesto,Fossa, Paola,Bruno, Olga
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p. 7061 - 7072
(2014/11/07)
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- Synthesis and Biological Evaluation of Chromenylurea and Chromanylurea Derivatives as Anti-TNF-a agents that Target the p38 MAPK Pathway
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A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-a production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-a release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).
- Li, Xingzhou,Zhou, Xinming,Zhang, Jing,Wang, Lili,Long, Long,Zheng, Zhibing,Li, Song,Zhong, Wu
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p. 2004 - 2028
(2014/03/21)
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- Synthesis of 3-(aminooxoethyl)-6-methyl-1-(thiethan-3-yl)-pyrimidine-2,4-(1H,3H)-diones
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A new approach to prepare 2-chloroacetamides has been developed, based on the reaction of chloroacetyl chloride with excess of secondary amines. Alkylation of 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione with the synthesized 2-chloroacetamides in the presence of potassium carbonate has afforded N 3-acetamido-substituted 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-diones.
- Meshcheryakova
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p. 1539 - 1542
(2015/02/19)
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- HEXAHYDROPYRROLOTHIAZINE COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R9 are as defined in the specification and which compound has an Αβ production inhibitory effect and may be useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Αβ and typified by Alzheimer-type dementia (AD) or Down's syndrome.
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(2014/02/15)
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