Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
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3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Wei-Kang Shi, Rui-Cheng Deng, Peng-Fei Wang, Qin-Qin Yue, Qi Liu, Kun-Ling Ding, Mei-Hui Yang, Hong-Yu Zhang, Si-Hua Gong, Min Deng, Wen-Run Liu, Qiu-Ju Feng, Zhu-Ping Xiao, Hai-Liang Zhu Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15±0.05μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12μg·mL−1 for K i and K i′, respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins. Graphical abstract image
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6-Aryl-4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside triphosphates (benzo-fused 7-deaza-dATP analogues): Synthesis, fluorescent properties, enzymatic incorporation into DNA and DNA-protein binding study ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Andrea Bosáková, Pavla Perlíková, Michal Tichý, Radek Pohl, Michal Hocek Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside triphosphates (dABXTPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335–378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein. Graphical abstract image
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Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase) ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Amy J. Rice, Hao Lei, Bernard D. Santarsiero, Hyun Lee, Michael E. Johnson Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (K D) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors. Graphical abstract image
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2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Georgia Antonopoulou, Victoria Magrioti, Maroula G. Kokotou, Aikaterini Nikolaou, Efrosini Barbayianni, Varnavas D. Mouchlis, Edward A. Dennis, George Kokotos Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. Graphical abstract image
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The human tyrosine kinase Kit and its gatekeeper mutant T670I, show different kinetic properties: Implications for drug design ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Miroslava Kissova, Giovanni Maga, Emmanuele Crespan The tyrosine kinase Kit, a receptor for Stem Cell Factor, is involved, among others, in processes associated to cell survival, proliferation and migration. Upon physiological conditions, the activity of Kit is tightly regulated. However, primary mutations that lead to its constitutive activation are the causal oncogenic driver of gastrointestinal stromal tumours (GISTs). GISTs are known to be refractory to conventional therapies but the introduction of Imatinib, a selective inhibitor of tyrosine kinases Abl and Kit, significantly ameliorated the treatment options of GISTs patients. However, the acquisition of secondary mutations renders Kit resistant towards all available drugs. Mutation involving gatekeeper residues (such as V654a and T670I) influence both the structure and the catalytic activity of the enzyme. Therefore, detailed knowledge of the enzymatic properties of the mutant forms, in comparison with the wild type enzyme, is an important pre-requisite for the rational development of specific inhibitors. In this paper we report a thorough kinetic analysis of the reaction catalyzed by the Kit kinase and its gatekeeper mutated form T670I. Our results revealed the different mechanisms of action of these two enzymes and may open a new avenue for the future design of specific Kit inhibitors. Graphical abstract image
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Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Arno Vermote, Gilles Brackman, Martijn D.P. Risseeuw, Tom Coenye, Serge Van Calenbergh Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure–activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues. Graphical abstract image
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In vitro cytotoxicity of novel 2,5,7-tricarbo-substituted indoles derived from 2-amino-5-bromo-3-iodoacetophenone ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Malose J. Mphahlele, Tshepiso J. Makhafola, Mmakwena M. Mmonwa A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki–Miyaura cross-coupling of 2-amino-5-bromo-3-iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl-substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways. Graphical abstract image
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Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Shaffali Singla, Poonam Piplani A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC50 =2.42μM) and antioxidant activity in comparison to donepezil (IC50 =1.82μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme. Graphical abstract image
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Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Rosania Yang, Maurício T. Tavares, Sarah F. Teixeira, Ricardo A. Azevedo, Diego C. Pietro, Thais B. Fernandes, Adilson K. Ferreira, Gustavo H.G. Trossini, José A.M. Barbuto, Roberto Parise-Filho A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure–activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G0/G1 cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization. Graphical abstract image
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Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Lei Fang, Minchang Feng, Feihong Chen, Xia Liu, Hong Shen, Jian Zhao, Shaohua Gou By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase. Graphical abstract image
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2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor: Synthesis, inhibitory activity, and mechanism ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Rui Wang, Wei-Ming Chai, Qin Yang, Man-Kun Wei, Yiyuan Peng 2-(4-Fluorophenyl)-quinazolin-4(3H)-one (FQ) was synthesized, and its structure was identified with 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), fourier transform infrared spectroscopy (FTIR), and high resolution mass spectrometry (HRMS). From the enzyme analysis, the results showed that it could inhibit the diphenolase activity of tyrosinase (IC50 =120±2μM). Furthermore, the results of kinetic studies showed that the compound was a reversible mixed-type inhibitor, and that the inhibition constants were determined to be 703.2 (K I) and 222.1μM (K IS). The results of fluorescence quenching experiment showed that the compound could interact with tyrosinase and the substrates (tyrosine and l-DOPA). Molecular docking analysis revealed that the mass transfer rate was affected by FQ blocking the enzyme catalytic center. In brief, current study identified a novel tyrosinase inhibitor which deserved further study for hyperpigmentation drugs. Graphical abstract image
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Structure–activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Xiaoli Xu, Yue Wu, Mingyang Hu, Xiang Li, Congying Gu, Qidong You, Xiaojin Zhang Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure–activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy. Graphical abstract image
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New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Hamada H.H. Mohammed, Amer Ali Abd El-Hafeez, Samar H. Abbas, El-Shimaa M.N. Abdelhafez, Gamal El-Din A. Abuo-Rahma New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC50 =14.8, 24.8, 23.6 and 20.7μM, respectively) compared to the parent ciprofloxacin (IC50 >100μM) and doxorubicin as a positive control (IC50 =1μM). The flow cytometric analysis for 2b showed dose dependent G2/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G2/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G2/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer. Graphical abstract image
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Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Ana L. Valenciano, Aaron C. Ramsey, Webster L. Santos, Zachary B. Mackey Human African trypanosomiasis (HAT) is a lethal, vector-borne disease caused by the parasite Trypanosoma brucei. Therapeutic strategies for this neglected tropical disease suffer from disadvantages such as toxicity, high cost, and emerging resistance. Therefore, new drugs with novel modes of action are needed. We screened cultured T. brucei against a focused kinase inhibitor library to identify promising bioactive compounds. Among the ten hits identified from the phenotypic screen, AZ960 emerged as the most promising compound with potent antiparasitic activity (IC50 =120nM) and was shown to be a selective inhibitor of an essential gene product, T. brucei extracellular signal-regulated kinase 8 (TbERK8). We report that AZ960 has a K i of 1.25μM for TbERK8 and demonstrate its utility in establishing TbERK8 as a potentially druggable target in T. brucei. Graphical abstract image
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Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Xian-Hai Lv, Zi-Li Ren, Ben-Guo Zhou, Qing-Shan Li, Ming-Jie Chu, Dao-Hong Liu, Kai Mo, Li-Song Zhang, Xiao-Kang Yao, Hai-Qun Cao Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization. Graphical abstract image
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Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Lauren E. Ragle, Dilip J. Palanisamy, Margaux J. Joe, Rachel S. Stein, Derek D. Norman, Gabor Tigyi, Daniel L. Baker, Abby L. Parrill Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4μM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1–5 GPCR. Graphical abstract image
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Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Michiyo Mochizuki, Masakuni Kori, Mitsunori Kono, Takahiko Yano, Yuu Sako, Maiko Tanaka, Naoyuki Kanzaki, Albert C. Gyorkos, Christopher P. Corrette, Kazuyoshi Aso A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50 =27nM, 56nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method. Graphical abstract image
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Design, synthesis, and biological evaluation of 1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of anti-prostate cancer agents ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Xiaojie Zhang, Rubing Wang, German Ruiz Perez, Guanglin Chen, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong Chen In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G0/G1 phase. Graphical abstract image
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CpG methylation increases the DNA binding of 9-aminoacridine carboxamide Pt analogues ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Hieronimus W. Kava, Vincent Murray This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5′-CpG sequences. Their binding to methylated and non-methylated 5′-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5′-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5′-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell’s genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use. Graphical abstract image
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Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3 ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Yutaka Nakajima, Naohiro Aoyama, Fumie Takahashi, Hiroshi Sasaki, Keiko Hatanaka, Ayako Moritomo, Masamichi Inami, Misato Ito, Koji Nakamura, Fumihiro Nakamori, Takayuki Inoue, Shohei Shirakami In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model. Graphical abstract image
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Synthesis and aromatase inhibitory evaluation of 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Zhidan Song, Yanchun Liu, Zhoutong Dai, Wei Liu, Kai Zhao, Tongcun Zhang, Yanying Hu, Xiuli Zhang, Yujie Dai In this paper, 13 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives were synthesized and their aromatase inhibitory activities were measured. The results show that the substitution of the groups on benzyl group can further improve their bioactivity and the compound with Cl on the para position of benzyl has the highest bioactivity (IC50 =9.02nM). A QSAR model was constructed from the 13 compounds with genetic function approximation using DS 2.1 package. This model can explain 90.09% of the variance (R 2 Adj), while it can predict 84.95% of the variance (R 2 cv) with the confidence interval of 95%. Graphical abstract image
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Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent anticancer chemopotentiating activity: Design, synthesis and biological evaluation ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Hui Li, Yan Hu, Xueyan Wang, Guangwei He, Yungen Xu, Qihua Zhu 8,9-Dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28nM in the PARP-1 and 7.7nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively. Graphical abstract image
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Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced Aβ aggregation and antioxidant ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Bo Wang, Zhiren Wang, Hong Chen, Chuan-Jun Lu, Xingshu Li A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1–42 aggregation, rapid H2O2 scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2 within 200–220min and possesses GPx-like activity (v 0 =106.0μM·min−1), enabling modulation of metal-induced Aβ aggregation. Graphical abstract image
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Novel small molecule binders of human N-glycanase 1, a key player in the endoplasmic reticulum associated degradation pathway ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Bharath Srinivasan, Hongyi Zhou, Sreyoshi Mitra, Jeffrey Skolnick Peptide:N-glycanase (NGLY1) is an enzyme responsible for cleaving oligosaccharide moieties from misfolded glycoproteins to enable their proper degradation. Deletion and truncation mutations in this gene are responsible for an inherited disorder of the endoplasmic reticulum-associated degradation pathway. However, the literature is unclear whether the disorder is a result of mutations leading to loss-of-function, loss of substrate specificity, loss of protein stability or a combination of these factors. In this communication, without burdening ourselves with the mechanistic underpinning of disease causation because of mutations on the NGLY1 protein, we demonstrate the successful application of virtual ligand screening (VLS) combined with experimental high-throughput validation to the discovery of novel small-molecules that show binding to the transglutaminase domain of NGLY1. Attempts at recombinant expression and purification of six different constructs led to successful expression of five, with three constructs purified to homogeneity. Most mutant variants failed to purify possibly because of misfolding and the resultant exposure of surface hydrophobicity that led to protein aggregation. For the purified constructs, our threading/structure-based VLS algorithm, FINDSITEcomb, was employed to predict ligands that may bind to the protein. Then, the predictions were assessed by high-throughput differential scanning fluorimetry. This led to the identification of nine different ligands that bind to the protein of interest and provide clues to the nature of pharmacophore that facilitates binding. This is the first study that has identified novel ligands that bind to the NGLY1 protein as a possible starting point in the discovery of ligands with potential therapeutic applications in the treatment of the disorder caused by NGLY1 mutants. Graphical abstract image
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Towards the PET radiotracer for p75 neurotrophin receptor: [11C]LM11A-24 shows biological activity in vitro, but unfavorable ex vivo and in vivo profile ()
Publication date: 1 October 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19 Author(s): Julien Gibon, Min Su Kang, Arturo Aliaga, Behrang Sharif, Pedro Rosa-Neto, Philippe Séguéla, Philip A. Barker, Alexey Kostikov Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75NTR) and sortilin. Aberrant expression of p75NTR in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease. The goal of this work was to evaluate one of the very few reported p75NTR small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75NTR imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75NTR. Based on this electrophysiological assay, the compound has very high potency with an EC50 <10nM. We optimized the radiosynthesis of [11C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75NTR. Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity. Graphical abstract image
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Biological evaluation of tetracationic compounds based on two 1,4-diazabicyclo[2.2.2]octane moieties connected by different linkers ()
Publication date: Available online 28 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Ekaterina A. Burakova, Irina V. Saranina, Nina V. Tikunova, Zhanna K. Nazarkina, Pavel P. Laktionov, Lubov’ A. Karpinskaya, Vadim B. Anikin, Vladimir V. Zarubaev, Vladimir N. Silnikov A series of 1,4-diazabicyclo[2.2.2]octane derivatives differing by linker moiety was evaluated for activity against several strains of both Gram-positive and Gram-negative bacteria including drug-resistant strains, one strain of fungus and influenza virus A/Puerto Rico/8/34 (H1N1). All compounds exhibited high antibacterial activity against all bacteria except Proteus vulgaris. The minimum inhibitory concentrations (MICs) of compound 1c with an o-phenylenebismethyl linker and compound 1e with a propylene aliphatic linker were found to be low and were comparable or better to the reference drug ciprofloxacin for Pseudomonas aeruginosa and Staphylococcus aureus. Additionally, a time-kill assay was performed to examine the bactericidal kinetics. Compounds 1c and 1e displayed rapid killing effects against St. aureus and Ps. aeruginosa after 2 h. Furthermore, compounds 1a–c with aromatic linkers and compound 1e showed the highest antiviral activity. Graphical abstract image
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Multitarget-directed oxoisoaporphine derivatives: anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity aagainst Alzheimer’s disease ()
Publication date: Available online 28 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Shenqi Wei, Wei Chen, Jingfang Qin, Yingzi Huangli, Li Wang, Yue Shen, Huang Tang A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood-brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ secretion levels. Moreover, one - third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically. Graphical abstract image
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Synthesis, photophysical properties and biological evaluation of β-alkylaminoporphyrin for photodynamic therapy ()
Publication date: Available online 26 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Ping-Yong Liao, Xin-Rong Wang, Ying-Hua Gao, Xiang-Hua Zhang, Li-Jun Zhang, Chun-Hong Song, Dan-Ping Zhang, Yi-Jia Yan, Zhi-Long Chen A series of β-alkylaminoporphyrins conjugated with different amines at βposition (D1 - D3) or with electron-donating and electron-withdrawing substituents at phenyl position (D4 - D6) were synthesized. Their photophysical and photochemical properties, intracellular localization, photocytotoxicities in vitro and vivo were also investigated. All target compounds exhibited no cytotoxicities in the dark and excellent photocytotoxicities against HeLa cells. Among them, D6 showed the highest phototoxicity and the lowest dark toxicity, which was more phototoxic than Hematoporphyrin monomethyl ether (HMME). In addition, D6 exhibited best photodynamic antitumor efficacy on BALB/c nude mice bearing HeLa tumor. Therefore, D6 is a powerful and promising antitumor photosensitizer for photodynamic therapy. Graphical abstract image
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Methylene versus Carbonyl Bridge in the Structure of New Tubulin Polymerization Inhibitors with Tricyclic A-Rings ()
Publication date: Available online 26 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Iuliana-Monica Moise, Elena Bîcu, Joëlle Dubois, Amaury Farce, Benoît Rigo, Alina Ghinet The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the “CH2” bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25 nM against the melanoma MDA-MB-435 cell line. Graphical abstract image
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Exploration of Bivalent Ligands Targeting Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Dimerization ()
Publication date: Available online 26 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Christopher K. Arnatt, Bethany A. Falls, Yunyun Yuan, Thomas J. Raborg, Ruturaj R. Masvekar, Nazira El-Hage, Dana E. Selley, Anthony V. Nicola, Pamela E. Knapp, Kurt F. Hauser, Yan Zhang Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation. Graphical abstract image
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Triethylated chromones with substituted naphthalenes as tubulin inhibitors ()
Publication date: Available online 25 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Kyoko Nakagawa-Goto, Yukako Taniguchi, Yurie Watanabe, Akifumi Oda, Emika Ohkoshi, Ernest Hamel, Kuo-Hsiung Lee, Masuo Goto Previously synthesized 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3–5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC50 0.2–5.7 μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin. Graphical abstract image
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Inhibition of the metastatic progression of breast and colorectal cancer in vitro and in vivo in murine model by the oxidovanadium (IV) complex with luteolin ()
Publication date: Available online 24 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Luciana G. Naso, Iker Badiola, Joana Marquez Clavijo, María Valcarcel, Clarisa Salado, Evelina G. Ferrer, Patricia A.M. Williams The anticancer and antimetastatic behavior of the flavonoid luteolin and its oxidovanadium(IV) complex [VO(lut)(H2O)2]Na.3H2O (VOlut) has been investigated. Considering that the complex displayed strong anticancer activity on MDAMB231 human breast cancer cell line we herein determined through in vitro assays that the complex would probably reduce breast cancer cell metastasis in a higher extent than the natural antioxidant. In the CT26 colon cancer cell line a stronger anticancer effect has also been determined for the complex (IC50 0.9 μM) and in addition it did not exert toxic effects on normal colon epithelial cells at concentrations up to 10 μM. Working with a murine model of highly aggressive, orthotopic colon cancer model (CT26 cancer cell lines) it has been determined that the complex might prevent metastatic dissemination of the colon cancer cells to the liver. The flavonoid luteolin also exerted anticancer effects (at a low degree, IC50 5.9 μM) on CT26 cell line and produced a 24% reduction of colon cancer liver metastasis. Graphical abstract image
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Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity ()
Publication date: Available online 24 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Francesca Curreli, Dmitry S. Belov, Ranjith Ramesh, Naisargi Patel, Andrea Altieri, Alexander V. Kurkin, Asim K. Debnath Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first in HIV-1 Env-pseudovirus based single-cycle infection assay as well as in a multi-cycle infection assay. Four of these new compounds showed much improved antiviral potency as well as cytotoxicity. We selected two of the best compounds 45A (NBD-14009) and 46A (NBD-14010) to test against a panel of 51 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates. These compounds showed noticeable breadth of antiviral potency with IC50 of as low as 150 nM. These compounds also inhibited cell-to-cell fusion and cell-to-cell HIV-1 transmission. The study is expected to pave the way of designing more potent and selective HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120. Graphical abstract image
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Synthesis and Biological Evaluation of Furocoumarin Derivatives on Melanin Synthesis in Murine B16 Cells for the Treatment of Vitiligo ()
Publication date: Available online 23 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Chao Niu, Guang Xian Pang, Gen Li, Jun Dou, Li Fei Nie, Helimay Himit, Madina Kabas, Haji Akber Aisa Furocoumarins, isolated from Psoralen corylifolia L., were found to be the most effective drug in the treatment of vitiligo nowadays. Twenty-five furocoumarin derivatives were thus designed and synthesized in order to improve the melanogenesis in B16 cells for the first time. Among them, twenty-three compounds were more potent than the positive control (8-MOP), the commonly used drug for vitiligo in clinic. Noticeably, compounds 6m (350.5%) and 6p (313.1%) based on the scaffold of 6k (2H-benzofuro[2,3-h]chromen-2-one) were nearly 3-fold stronger than 8-MOP (114.50%). The in vitro melanin synthesis evaluation of these structurally diverse analogues had also led to an outline of structure-activity relationship. Graphical abstract image
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Syntheses and mucosal adjuvant activity of simplified oleanolic acid saponins possessing cinnamoyl ester ()
Publication date: Available online 22 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Tatsuya Shirahata, Takayuki Nagai, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Naruki Konishi, Takashi Nishino, Kazuishi Makino, Haruki Yamada, Eisuke Kaji, Hiroaki Kiyohara, Yoshinori Kobayashi A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant. Graphical abstract image
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A cell-based approach to characterize antimicrobial compounds through kinetic dose response ()
Publication date: Available online 22 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Craig R. MacNair, Jonathan M. Stokes, Shawn French, Cullen L. Myers, Kali R. Iyer, Eric D. Brown The rapid spread of antibiotic resistance has created a pressing need for the development of novel drug screening platforms. Herein, we report on the use of cell-based kinetic dose response curves for small molecule characterization in antibiotic discovery efforts. Kinetically monitoring bacterial growth at sub-inhibitory concentrations of antimicrobial small molecules generates unique dose response profiles. We show that clustering of profiles by growth characteristics can classify antibiotics by mechanism of action. Furthermore, changes in growth kinetics have the potential to offer insight into the mechanistic action of novel molecules and can be used to predict off-target effects generated through structure-activity relationship studies. Kinetic dose response also allows for detection of unstable compounds early in the lead development process. We propose that this kinetic approach is a rapid and cost-effective means to gather critical information on antimicrobial small molecules during the hit selection and lead development pipeline. Graphical abstract image
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Design and synthesis of purine analogues as highly specific ligands for FcyB, a ubiquitous fungal nucleobase transporter ()
Publication date: Available online 22 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Nikolaos Lougiakis, Efthymios-Spyridon Gavriil, Markelos Kairis, Georgia Sioupouli, George Lambrinidis, Dimitra Benaki, Emilia Krypotou, Emmanuel Mikros, Panagiotis Marakos, Nicole Pouli, George Diallinas In the course of our study on fungal purine transporters, a number of new 3-deazapurine analogues have been rationally designed, based on the interaction of purine substrates with the Aspergillus nidulans FcyB carrier, and synthesized following an effective synthetic procedure. Certain derivatives have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. Molecular simulations have been performed, suggesting that all active compounds interact with FcyB through the formation of hydrogen bonds with Asn163, while the insertion of hydrophobic fragments at position 9 and N6 of 3-deazaadenine enhanced the inhibition. Graphical abstract image
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Insights into tyrosinase inhibition by compounds isolated from Greyia radlkoferi Syzsyl using biological activity, molecular docking and gene expression analysis ()
Publication date: Available online 22 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Namrita Lall, Elizabeth Mogapi, Marco Nuno de Canha, Bridget Crampton, Mabatho Nqephe, Ahmed Hussein, Vivek Kumar Greyia radlkoferi ethanol extract and its five compounds were tested for their inhibitory activity against the mushroom tyrosinase enzyme and melanin production on melanocytes. The crude extract showed significant tyrosinase inhibition with IC50 of 17.96μg/ml. This is the first report of the isolation of these 5 compounds from Greyia radlkoferi. 2’, 4’, 6’-trihydroxydihydrochalcone showed the highest tyrosinase inhibition at 17.70μg/ml (68.48μM), with low toxicity when compared with crude extract. This compound is therefore, a key component in the crude extract, which is responsible for tyrosinase inhibitory activity. The RT-qPCR indicated that the mechanism of action is most likely post transcriptional. Further, the molecular docking study showed that tyrosinase inhibitory activity depends on interaction of the compound with Cu2+ ions at the active site. This is the first report of the tyrosinase inhibitory activity of the G. radlkoferi extract and molecular insights on interaction of its compounds with Cu2+ ions as the driving factor for tyrosinase inhibition. These results suggest that the extract of G. radlkoferi and the compound 2’, 4’, 6’-trihydroxydihydrochalcone have great potential to be further developed as pharmaceutical or cosmetic agents for use against dermatological disorders associated with melanin. Graphical abstract image
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Synthesis and Topoisomerases Inhibitory Activity of heteroaromatic chalcones ()
Publication date: Available online 21 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Kyung-Hwa Jeon, Han-Bit Yu, Soo Yeon Kwak, Youngjoo Kwon, Younghwa Na The critical role of nuclear enzyme topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds’ pharmacological efficacy. In the topoisomerase I inhibitory test, compound 1 was most active one, 24% of inhibition at 20 μM, among all the compounds but it was lower than camptothecin. Compounds 9, 11, and 13 inhibited the function of topoisomerase II more strongly than etoposide with almost same magnitude (around 90% and 30% inhibition at 100 and 20 μM, respectively) which were higher than those of etoposide (72% and 18% inhibition). In the cytotoxicity test, compound 9 inhibited T47D cancer cell growth with the IC50 value of 6.61 ± 0.21 μM. On the other hand, compound 13 (IC50: 4.32 ± 0.18 μM) effectively suppressed MDA-MB468 cancer cell growth. Graphical abstract image
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Synthesis and Pin1 inhibitory activity of thiazole derivatives ()
Publication date: Available online 21 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Hailong Zhao, Guonan Cui, Jing Jin, Xiaoguang Chen, Bailing Xu Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its subtrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activites were measured agaist human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC50 values at low micromolar level. The detailed structure–activity relationships were analyzed and the binding features of compound 10b (IC50 5.38 μM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors. Graphical abstract image
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Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson’s disease ()
Publication date: Available online 21 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Zhimin Wang, Jiajia Wu, Xuelian Yang, Pei Cai, Qiaohong Liu, Kelvin D.G. Wang, Lingyi Kong, Xiaobing Wang The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson’s disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson’s disease therapy. Graphical abstract image
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Not just an antibiotic target: exploring the role of type I signal peptidase in bacterial virulence ()
Publication date: Available online 21 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Shawn Walsh, Arryn Craney, Floyd E. Romesberg The looming antibiotic crisis has prompted the development of new strategies towards fighting infection. Traditional antibiotics target bacterial processes essential for viability, whereas proposed antivirulence approaches rely on the inhibition of factors that are required only for the initiation and propagation of infection within a host. Although antivirulence compounds have yet to prove their efficacy in the clinic, bacterial signal peptidase I (SPase) represents an attractive target in that SPase inhibitors exhibit broad-spectrum antibiotic activity, but even at sub-MIC doses also impair the secretion of essential virulence factors. The potential consequences of SPase inhibition on bacterial virulence have not been thoroughly examined, and are explored within this review. In addition, we review growing evidence that SPase has relevant biological functions outside of mediating secretion, and discuss how the inhibition of these functions may be clinically significant. Graphical abstract image
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Synthesis and antimicrobial activity of small cationic amphipathic aminobenzamide marine natural product mimics and evaluation of relevance against clinical isolates including ESBL-CARBA multi-resistant bacteria ()
Publication date: Available online 20 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Elizaveta M. Igumnova, Ekaterina Mishchenko, Tor Haug, Hans-Matti Blencke, Johanna U. Ericson Sollid, Elizabeth G. Aarag Fredheim, Silje Lauksund, Klara Stensvåg, Morten B. Strøm A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5 – 2 μg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE). E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL-CARBA multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds. Graphical abstract image
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Synthesis and Structure–Activity Relationships of 1-Benzylindane Derivatives as Selective Agonists for Estrogen Receptor Beta ()
Publication date: Available online 20 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Shigeru Yonekubo, Nobuhiko Fushimi, Takashi Miyagi, Osamu Nakanishi, Kenji Katsuno, Motoyasu Ozawa, Chiaki Handa, Noritaka Furuya, Hideyuki Muranaka The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERβ ligands. In this study, we evaluated the selective ERβ agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure–activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERβ (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R -12a has a superior profile over S -12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERβ agonists and indicates that this indane-based scaffold has the potential to provide better ERβ agonistic probes. Graphical abstract image
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Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential ()
Publication date: Available online 20 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Sergey S. Laev, Nariman F. Salakhutdinov, Olga I. Lavrik DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3′- or 5′-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed. Graphical abstract image
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A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities ()
Publication date: Available online 19 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Chelliah Bharkavi, Sundaravel Vivek Kumar, Mohamed Ashraf Ali, Hasnah Osman, Shanmugam Muthusubramanian, Subbu Perumal A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC50 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC50 <1.56μM) and 6l (IC50 =2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC50 values of 1.10 and 1.16μmol/L respectively. Graphical abstract image
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Design, synthesis and biological evaluation of potential antibacterial butyrolactones ()
Publication date: Available online 17 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Alaa Sweidan, Marylene Chollet-Krugler, Pierre van de Weghe, Ali Chokr, Sophie Tomasi, Martine Bonnaure-Mallet, Latifa Bousarghin Novel butyrolactone analogues were designed and synthesized based on the known lichen antibacterial compounds, lichesterinic acids (B-10 and B-11), by substituting different functional groups on the butyrolactone ring trying to enhance its activity. All synthesized butyrolactone analogues were evaluated for their in vitro antibacterial activity against Streptococcus gordonii. Among the derivatives, B-12 and B-13 had the lowest MIC of 9.38μg/mL where they have shown to be stronger bactericidals, by 2–3 times, than the reference antibiotic, doxycycline. These two compounds were then checked for their cytotoxicity against human gingival epithelial cell lines, Ca9–22, and macrophages, THP-1, by MTT and LDH assays which confirmed their safety against the tested cell lines. A preliminary study of the structure–activity relationships unveiled that the functional groups at the C4 position had an important influence on the antibacterial activity. An optimum length of the alkyl chain at the C5 position registered the best antibacterial inhibitory activity however as its length increased the bactericidal effect increased as well. This efficiency was attained by a carboxyl group substitution at the C4 position indicating the important dual role contributed by these two substituents which might be involved in their mechanism of action. Graphical abstract image
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Quinazolinone derivatives: synthesis and comparison of inhibitory mechanisms on α-glucosidase ()
Publication date: Available online 17 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Mankun Wei, Wei-Ming Chai, Rui Wang, Qin Yang, Zhihong Deng, Yiyuan Peng In this study, eight quinazolinone derivatives were designed and synthesized. Their inhibitory activities on α-glucosidase were assessed in vitro. Two compounds: 2-(4-chlorophenyl)-quinazolin-4(3H)-one (CQ) and 2-(4-bromophenyl)-quinazolin-4(3H)-one (BQ) were found to be potent inhibitors of α-glucosidase with IC50 values of 12.5 ± 0.1 μM and 15.6 ± 0.2 μM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The results revealed that they reversibly inhibited α-glucosidase in a non-competitive manner. CQ and BQ could statically quench the fluorescence spectra by formation of an inhibitor-α-glucosidase complex. The interaction between CQ and α-glucosidase depended on hydrogen bonds, electrostatic and hydrophobic force, while the driving force of the binding between BQ and the enzyme was hydrophobic. The docking results showed that BQ was less active than CQ against α-glucosidase because of its weaker interaction with the enzyme. In brief, the quinazolinone derivatives identified in this work were potentially promising candidates for developing as novel anti-diabetic agents. Graphical abstract image
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Design, synthesis and evaluation of anti-CD123 antibody drug conjugates ()
Publication date: Available online 17 September 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Bin Li, Weiyu Zhao, Xinfu Zhang, Junfeng Wang, Xiao Luo, Sharyn D. Baker, Craig T. Jordan, Yizhou Dong Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment. Graphical abstract image
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