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Bioorganic & Medicinal Chemistry

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https://www.readbyqxmd.com/read/28533113/a-novel-serine-racemase-inhibitor-suppresses-neuronal-over-activation-in-vivo
#1
Hisashi Mori, Ryogo Wada, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tetsuya Ishimoto, Tomoyuki Yoshida, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka
Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states...
May 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28526475/identification-and-preliminary-structure-activity-relationships-of-1-indanone-derivatives-as-novel-indoleamine-2-3-dioxygenase-1-ido1-inhibitors
#2
Dingding Gao, Yingxia Li
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer's disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein...
May 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522267/synthesis-of-novel-acyl-selenoureido-benzensulfonamides-as-carbonic-anhydrase-i-ii-vii-and-ix-inhibitors
#3
Andrea Angeli, Fabrizio Carta, Gianluca Bartolucci, Claudiu T Supuran
A novel series of acyl selenoureido benzensulfonamides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, VII and IX, which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy and tumors etc. These compounds showed excellent inhibitory activity for these isoforms, with several low nanomolar derivatives identified against all of them. Furthermore, the selenoureido group may provide an antioxidant activity to these enzyme inhibitors...
May 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522268/design-and-synthesis-of-novel-photoinduced-electron-transfer-based-hybridization-probes
#4
Chika Yokoyama, Kosuke Nakamoto, Yoshihito Ueno
Photoinduced electron transfer (PeT)-based hybridization probe is a linear and quencher-free oligonucleotide (ON) probe for DNA or RNA detection. In this report, we designed and synthesized novel adenosine analogues for PeT-based hybridization probe. In particular, the analogue containing a piperazinomethyl moiety showed effective quenching property under physiological conditions. When the probe containing the analogue was hybridized with a complementary DNA or RNA, the fluorescence increased 3- or 4-fold, respectively, compared to the single-stranded state...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522265/screening-for-bioactive-natural-products-from-a-67-compound-library-of-glycyrrhiza-inflata
#5
Yan Lin, Yi Kuang, Kai Li, Shuang Wang, Wei Song, Xue Qiao, Gulnar Sabir, Min Ye
Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522264/discovery-synthesis-and-structure-activity-relations-of-3-4-dihydro-1h-spiro-naphthalene-2-2-piperidin-1-ones-as-potassium-competitive-acid-blockers
#6
Toshihiro Imaeda, Koji Ono, Kazuo Nakai, Yasunobu Hori, Jun Matsukawa, Terufumi Takagi, Yasushi Fujioka, Naoki Tarui, Mitsuyo Kondo, Akio Imanishi, Nobuhiro Inatomi, Masahiro Kajino, Fumio Itoh, Haruyuki Nishida
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H(+),K(+)-ATPase and can strongly bind to the K(+)-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H(+),K(+)-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28511911/sulfonamide-inhibition-profiles-of-the-%C3%AE-carbonic-anhydrase-from-the-pathogenic-bacterium-francisella-tularensis-responsible-of-the-febrile-illness-tularemia
#7
Sonia Del Prete, Daniela Vullo, Sameh M Osman, Zeid AlOthman, Claudiu T Supuran, Clemente Capasso
A new β-class carbonic anhydrase (CA, EC 4.2.1.1) has been cloned, purified and characterized in the genome of the pathogenic bacterium Francisella tularensis responsible of the febrile illness tularemia. This enzyme, FtuβCA, showed a kcat of 9.8 ×10(5)s(-1) and a kcat/KM of 8.9 ×10(7)M(-1)s(-1) for the CO2 hydration, physiological reaction, being one of the most effective β-CAs known to date, with a catalytic activity only 1.68-times lower than that of the human(h) isoform hCA II. A panel of 39 simple aromatic and heterocyclic sulfonamides, as well as clinically used drugs incorporating sulfonamide/sulfamate zinc-binding groups, was used to investigate the inhibition profile of FtuβCA with these classes of derivatives...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28511908/potential-anti-gout-constituents-as-xanthine-oxidase-inhibitor-from-the-fruits-of-stauntonia-brachyanthera
#8
Dan Liu, Dandan Wang, Wei Yang, Dali Meng
With the aim of finding a better xanthine oxidase inhibitor with potential anti-gout properties, the studies on the fruit of Stauntonia brachyanthera were carried out, which led to the isolation of 12 glycosides, including 4 new nor-oleanane triterpenoids. Their structures were determined by comprehensive spectroscopic (NMR and HR MS) analysis. Two compounds (4 and 11) exhibited significant inhibitory activities on xanthine oxidase with IC50 values of 5.22 and 1.60µM, respectively. Another five compounds (1, 2, 3, 8 and 10) showed qualified activities...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28526476/revisiting-ligation-at-selenomethionine-insights-into-native-chemical-ligation-at-selenocysteine-and-homoselenocysteine
#9
Rebecca Notis Dardashti, Norman Metanis
Selenomethionine (Sem) has been incorporated recombinantly into proteins many times to elucidate their structure and function. In this paper, we revisit incorporation via chemical protein synthesis to shed light on the mechanism of native chemical ligation. The effect of chalcogen position on ligation is investigated, and selenium-containing peptide ligation is optimized. Additionally, selective methylation is performed on selenolates in a peptide in the presence of unprotected thiols.
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522266/site-specific-conjugation-of-fibroblast-growth-factor-2-fgf2-based-on-incorporation-of-alkyne-reactive-unnatural-amino-acid
#10
K W Swiderska, A Szlachcic, A Czyrek, M Zakrzewska, J Otlewski
Recent advances in site-specific protein modification include the increasingly popular incorporation of unnatural amino acid(s) using amber codon, a method developed by Schultz and coworkers. In this study, we employ this technique to introduce propargyllysine (PrK) in human fibroblast growth factor 2 (FGF2). Owing to an alkyne moiety in its side chain, PrK is compatible with Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). We successfully tested CuAAC-mediated conjugation of FGF2 with two compounds - a fluorophore carboxyrhodamine 110 or a cytotoxic drug monomethyl auristatin E (MMAE)...
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28511909/discovery-and-structure-guided-fragment-linking-of-4-2-3-dichlorobenzoyl-1-methyl-pyrrole-2-carboxamide-as-a-pyruvate-kinase-m2-activator
#11
Yumi Matsui, Isao Yasumatsu, Takashi Asahi, Takahiro Kitamura, Kazuo Kanai, Osamu Ubukata, Hitoshi Hayasaka, Sachiko Takaishi, Hiroyuki Hanzawa, Shinichi Katakura
Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS)...
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28511907/potential-inhibitors-of-human-carbonic-anhydrase-isozymes-i-and-ii-design-synthesis-and-docking-studies-of-new-1-3-4-thiadiazole-derivatives
#12
Mehlika Dilek Altıntop, Belgin Sever, Ahmet Özdemir, Kaan Kucukoglu, Hicran Onem, Hayrunnisa Nadaroglu, Zafer Asım Kaplancıklı
In the last years, inhibition of carbonic anhydrase (CA) has emerged as a promising approach for pharmacologic intervention in a variety of disorders such as glaucoma, epilepsy, obesity, and cancer. As a consequence, the design of CA inhibitors (CAIs) is a highly dynamic field of medicinal chemistry. Due to the therapeutic potential of thiadiazoles as CAIs, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their inhibitory effects on hCA I and hCA II. Although the tested compounds did not carry a sulfonamide group, an important pharmacophore for CA inhibitory activity, it was a remarkable finding that most of them were more effective on hCAs than acetazolamide (AAZ), the reference agent...
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28529043/the-impact-of-the-halogen-bonding-on-d2-and-5-ht1a-5-ht7-receptor-activity-of-azinesulfonamides-of-4-2-ethyl-piperidinyl-1-yl-phenylpiperazines-with-antipsychotic-and-antidepressant-properties
#13
Anna Partyka, Rafał Kurczab, Vittorio Canale, Grzegorz Satała, Krzysztof Marciniec, Agnieszka Pasierb, Magdalena Jastrzębska-Więsek, Maciej Pawłowski, Anna Wesołowska, Andrzej J Bojarski, Paweł Zajdel
A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28528081/click-strategy-using-disodium-salts-of-amino-acids-improves-the-water-solubility-of-plinabulin-and-kpu-300
#14
Fumika Yakushiji, Kyohei Muguruma, Yoshiki Hayashi, Takuya Shirasaka, Ryosuke Kawamata, Hironari Tanaka, Yushi Yoshiwaka, Akihiro Taguchi, Kentaro Takayama, Yoshio Hayashi
Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28511910/synthesis-and-biological-research-of-novel-azaacridine-derivatives-as-potent-dna-binding-ligands-and-topoisomerase-ii-inhibitors
#15
Dan Li, Zigao Yuan, Shaopeng Chen, Cunlong Zhang, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28506582/dual-functional-small-molecule-fluorescent-probes-for-image-guided-estrogen-receptor-specific-targeting-coupled-potent-antiproliferative-potency-for-breast-cancer-therapy
#16
Lu Yang, Zhiye Hu, Junjie Luo, Chu Tang, Silong Zhang, Wentao Ning, Chune Dong, Jian Huang, Xianjun Liu, Hai-Bing Zhou
A strategy by integrating biological imaging into early stages of the drug discovery process can improve our understanding of drug activity during preclinical and clinical study. In this article, we designed and synthesized coumarin-based nonsteroidal type fluorescence ligands for drug-target binding imaging. Among these synthesized compounds, 3e, 3f and 3h showed potent ER binding affinity and 3e (IC50=0.012μM) exhibited excellent ERα antagonistic activity, its antiproliferative potency in breast cancer MCF-7 cells is equipotent to the approved drug tamoxifen...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28502459/discovery-of-indolin-2-one-derivatives-as-potent-pak4-inhibitors-structure-activity-relationship-analysis-biological-evaluation-and-molecular-docking-study
#17
Jing Guo, Mingyue Zhu, Tianxiao Wu, Chenzhou Hao, Kai Wang, Zizheng Yan, Wanxu Huang, Jian Wang, Dongmei Zhao, Maosheng Cheng
Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50=22nM, 16nM and 27nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50=0.83μM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth...
May 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28501430/kinetic-properties-and-affinities-for-sulfonamide-inhibitors-of-an-%C3%AE-carbonic-anhydrase-cruca4-involved-in-coral-biomineralization-in-the-mediterranean-red-coral-corallium-rubrum
#18
Sonia Del Prete, Daniela Vullo, Didier Zoccola, Sylvie Tambutté, Clemente Capasso, Claudiu T Supuran
We report the kinetic properties and sulfonamide inhibition profile of an α-carbonic anhydrase (CA, EC 4.2.1.1), named CruCA4, identified in the red coral Corallium rubrum. This isoform is involved in the biomineralization process leading to the formation of a calcium carbonate skeleton. Experiments performed on the recombinant protein show that the enzyme has a "moderate activity" level. Our results are discussed compared to values obtained for other CA isoforms involved in biomineralization. This is the first study describing the biochemical characterization of an octocoral CA...
May 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28533114/2-aminomethylthieno-3-2-d-pyrimidin-4-3h-ones-bearing-3-methylpyrazole-hinge-binding-moiety-highly-potent-selective-and-time-dependent-inhibitors-of-cdc7-kinase
#19
Osamu Kurasawa, Misaki Homma, Yuya Oguro, Tohru Miyazaki, Kouji Mori, Noriko Uchiyama, Kenichi Iwai, Akihiro Ohashi, Hideto Hara, Sei Yoshida, Nobuo Cho
In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity...
May 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28506585/c21-steroidal-pregnane-sapogenins-and-their-derivatives-as-anti-inflammatory-agents
#20
Lie-Jun Huang, Shao-Ru Chen, Chun-Mao Yuan, Wei Gu, Bao-Jian Guo, Yi-Tao Wang, Ying Wang, Xiao-Jiang Hao
During the screening of natural anti-inflammatory agent, we identified some C21-steroidal pregnane sapogenins or the derivatives to inhibit TLR2, TLR3, and TLR4-initiatedinflammatory responses respectively. Treatment with active compounds 10, 2j and 3p failed to impact tumor necrosis factor-α (TNF-α) induced nucleus translocation of NF-κB p65 subunit. However, these compounds regulated distinct canonical or non-canonical NF-κB family members. Ectopic expression of TNF receptor associated factor 6 (TRAF6) abrogated the inhibitory activity of the compounds on production of pro-inflammatory cytokines downstream of TLR4...
May 2, 2017: Bioorganic & Medicinal Chemistry
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