共查询到20条相似文献,搜索用时 31 毫秒
1.
Brian C. Shook Stefanie Rassnick Devraj Chakravarty Nathaniel Wallace Mark Ault Jeffrey Crooke J. Kent Barbay Aihua Wang Kristi Leonard Mark T. Powell Vernon Alford Daniel Hall Kenneth C. Rupert Geoffrey R. Heintzelman Kristen Hansen James L. Bullington Robert H. Scannevin Karen Carroll Lisa Lampron Lori Westover Paul F. Jackson 《Bioorganic & medicinal chemistry letters》2010,20(9):2868-2871
Two reactive metabolites were identified in vivo for the dual A2A/A1 receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity. 相似文献
2.
《Bioorganic & medicinal chemistry》2016,24(10):2273-2279
SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC–MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a–e and used them as references to confirm the structures of the two metabolites detected by LC–MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites. 相似文献
3.
Emiliano Manzo M. Letizia Ciavatta Salem Bakkas Guido Villani Mario Varcamonti Anna Zanfardino Margherita Gavagnin 《Phytochemistry letters》2009,2(4):211-215
Analysis of the secondary metabolites content of the brown alga Dictyota ciliolata, collected from Oualidia lagoon (Morocco), revealed the presence of xenicane and guaiane homologous diterpenes. Two new xenicanes, 1 and 2, co-occurring with the known dictyodial, dictyol C and dictyol H, have been isolated and characterized by spectral methods, mainly by NMR techniques. Compound 2 displayed mild antifungal activity against Candida albicans. 相似文献
4.
Fish PV Barta NS Gray DL Ryckmans T Stobie A Wakenhut F Whitlock GA 《Bioorganic & medicinal chemistry letters》2008,18(15):4355-4359
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration. 相似文献
5.
Katsushi Kumata Akiko Hatori Tomoteru Yamasaki Yiding Zhang Wakana Mori Masayuki Fujinaga Lin Xie Nobuki Nengaki Ming-Rong Zhang 《Bioorganic & medicinal chemistry》2019,27(3):483-491
Metabotropic glutamate receptor 2 (mGluR2) has been suggested as a therapeutic target for treating schizophrenia-like symptoms arising from increased glutamate transmission in the human forebrain. However, no reliable positron emission tomography (PET) radiotracer allowing for in vivo visualization of mGluR2 in the human brain is currently available. In this study, we synthesized 4-(2-fluoro-4-[11C]methoxyphenyl)-5-((2-methylpyridin-4-yl)methoxy)picolinamide ([11C]1) and evaluated its potential as a PET tracer for imaging mGluR2 in the rodent brain. Compound 1, a negative allosteric modulator (NAM) of mGluR2, showed high in vitro binding affinity (IC50: 26?nM) for mGluR2 overexpressed in human cells. [11C]1 was synthesized by O-[11C]methylation of the phenol precursor 2 with [11C]methyl iodide. After the reaction, HPLC purification and formulation, [11C]1 of 7.4?±?2.8?GBq (n?=?8) was obtained from [11C]carbon dioxide of 22.5?±?4.8?GBq (n?=?8) with >99% radiochemical purity and 70?±?32?GBq/μmol (n?=?8) molar activity at the end of synthesis. In vitro autoradiography for rat brains showed that [11C]1 binding was heterogeneously distributed in the cerebral cortex, striatum, hippocampus, and cerebellum. This pattern is consistent with the regional distribution pattern of mGluR2 in the rodent brain. The radioactivity was significantly reduced by self- or MNI-137 (a mGluR2 NAM) blocking. Small-animal PET studies indicated a low in vivo specific binding of [11C]1 in the rat brain. The brain uptake was increased in a P-glycoprotein and breast cancer resistant protein double knockout mouse, when compared to a wild-type mouse. While [11C]1 presented limited potential as an in vivo PET tracer for mGluR2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties. 相似文献
6.
《Journal of Molecular Catalysis .B, Enzymatic》2011,68(3-4):251-256
Microbial transformation of the steroidal sapogenin diosgenin (1) by resting cells of the filamentous fungus, Cunninghamella echinulata CGMCC 3.2716 was studied. Four metabolites were isolated and unambiguously characterized as (25R)-spirost-5-ene-3β,7β-diol-11-one (2), (25R)-spirost-5-ene-3β,7β-diol (3), (25R)-spirost-5-ene-3β,7β,11α-triol (4), and (25R)-spirost-5-ene-3β,7β,12β-triol (5), by various spectroscopic methods (1H, 13C NMR, DEPT, 1H–1H COSY, HMBC, HSQC and NOESY). Compound 2 is a new metabolite. The NMR data and full assignment for the known metabolites (25R)-spirost-5-ene-3β,7β-diol (3) and (25R)-spirost-5-ene-3β,7β,11α-triol (4) are described here for the first time. The biotransformation characteristics observed included were C-7β, C-11α and C-12β hydroxylations. Compounds 1–5 exhibited no significant cytotoxic activity to human glioma cell line U87. 相似文献
7.
《Bioorganic & medicinal chemistry》2014,22(21):6297-6304
We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 μg/mL) and 11 (IC50 of 0.64 μg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo. 相似文献
8.
Dalea pogonathera A. Gray was collected as part of a project to determine if metabolites of the genus Dalea have potential for the treatment of human hookworm disease, based on earlier findings of very active materials in D. ornata. We report here the isolation, characterization, and results of ex vivo bioassays of a new chalcone pogonatheridin A (1), and three new prenylated flavanones (3, 6, and 12). The isolated known compounds, a chalcone (2), flavanones (4,5,7-11,13,14), and a flavan-3-ol (15), were also examined. Pogonatheridin A (1) reduced the survival of the adults of Ancylostoma ceylanicum hookworm by 12.5 % (50 μg/mL), while all other compounds showed very weak or no activity. The compounds were tested (50 μg/mL) for toxicity to healthy mammalian cells. Seven of them (2-8) showed > 98 % reduction in survival of splenocytes, while 1 was somewhat less toxic at 74.3 % reduction in survival. While metabolites of D. pogonathera did not show promise as potential anthelmintics for hookworm disease, the toxicity information is of interest, and the rich diversity of metabolites of Dalea spp. remains apparent. 相似文献
9.
Yan Sun Dan Liu RongGang Xi Xiaobo Wang Yan Wang Jie Hou Baojing Zhang Changyuan Wang Kexin Liu Xiaochi Ma 《Bioorganic & medicinal chemistry letters》2013,23(5):1338-1342
The capabilities of 20 strains of fungi to transform acetyl-11-keto-β-boswellic (AKBA) were screened. And biotransformation of AKBA by Cunninghamella blakesleana AS 3.970 afforded five metabolites (1–5), while two metabolites (6, 7) were isolated from biotransformation of Cunninghamella elegans AS 3.1207. The chemical structures of these metabolites were identified by spectral methods including 2D NMR and their structures were elucidated as 7β-hydroxy-3-acety-11-keto-β-boswellic acid (1), 21β-dihydroxy-3-acety-11-keto-β-boswellic acid (2), 7β,22α-dihydroxy-3-acety-11-keto-β-boswellic acid (3), 7β,16α-dihydroxy-3-acety-11-keto-β-boswellic acid (4), 7β,15α-dihydroxy-3-acety-11-keto-β-boswellic acid (5); 7β,15α,21β-trihydroxy-3-acety-11-keto-β-boswellic acid (6) and 15α,21β-dihydroxy-3-acety-11-keto-β-boswellic acid (7). All these products are previously unknown. Their primary structure–activity relationships (SAR) of inhibition activity on LPS-induced NO production in RAW 264.7 macrophage cells were evaluated. 相似文献
10.
S.N. Suryawanshi Santosh Kumar Avinash Tiwari Rahul Shivahare Yashpal Singh Chhonker Susmita Pandey Nishi Shakya Rabi Sankar Bhatta Suman Gupta 《Bioorganic & medicinal chemistry letters》2013,23(13):3979-3982
A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5 μM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes. 相似文献
11.
《Bioorganic & medicinal chemistry》2020,28(11):115527
Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated. Their structures were elucidated by spectroscopic analysis and theoretical calculations. The enzyme-based assays indicated that 1 and 13 showed strong (+++) and moderate (++) TOP1 inhibition, respectively. Two chalcone derivatives 11 and 12 were firstly found as dual TDP1 and TOP1 natural inhibitors, and showed synergistic effect with the clinical TOP1 inhibitors topotecan in MCF-7 cells. Compounds 8, 16, and 22 acted as TOP1 catalytic inhibitors with equipotent TOP1 inhibition to camptothecin (++++). Compounds 7 and 8 exhibited significant cytotoxicity against MCF-7, A549, and HCT116 cells with GI50 values in the range of 2.2–4.8 μM. This work would provide valuable information that secondary metabolites from I. ternifolius could be developed as anticancer agents. 相似文献
12.
Ai-Hong Liu Ding-Quan Liu Tong-Jun Liang Xiao-Qing Yu Mei-Tang Feng Li-Gong Yao Yi Fang Bin Wang Li-Hua Feng Min-Xian Zhang Shui-Chun Mao 《Bioorganic & medicinal chemistry letters》2013,23(9):2491-2494
Two new prenylated para-xylenes, named caulerprenylols A (1) and B (2), were isolated from the green alga Caulerpa racemosa, collected from the Zhanjiang coastline, China. The structures of the two metabolites were elucidated on the basis of detailed spectroscopic analysis. This is the first report of prenylated para-xylenes from marine algae and from marine organisms as well. Moreover, caulerprenylol B (2) is also characterized by an uncommon indane ring system. In in vitro bioassays, the new compounds exhibited a broad spectrum of antifungal activity against Candida glabrata (537), Trichophyton rubrum (Cmccftla), and Cryptococcus neoformans (32609) with MIC80 values between 4 and 64 μg/mL when compared to amphotericin B (MIC80 values of 2.0, 1.0, and 4.0 μg/mL, respectively) as a positive control and showed no growth inhibition activity against the tumor cells HL60 and A549. 相似文献
13.
Yoko Shimoda Joji Yui Lin Xie Masayuki Fujinaga Tomoteru Yamasaki Masanao Ogawa Nobuki Nengaki Katsushi Kumata Akiko Hatori Kazunori Kawamura Ming-Rong Zhang 《Bioorganic & medicinal chemistry》2013,21(17):5316-5322
1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki = 2.6 nM) with a low binding affinity for the 5-HT1A receptor (Ki = 476 nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [11C]4 was synthesized at high radiochemical yield and specific activity, by O-[11C]methylation of 2′-(piperazin-1-yl)-[1,1′-biphenyl]-4-ol (6) with [11C]methyl iodide. Autoradiography revealed that [11C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [11C]4 in the brain exceeded 90% of the radioactive components at 15 min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [11C]4 in the brain (1.2 SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [11C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(5):1421-1425
Many adamantane derivatives have been demonstrated to function as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. 3-Amino-N-adamantyl-3-methylbutanamide derivatives were optimized by structure-based drug design. Compound 8j exhibited a good in vitro and ex vivo inhibitory activity against both human and mouse 11β-HSD1. 相似文献
15.
Masayuki Fujinaga Katsushi Kumata Kazuhiko Yanamoto Kazunori Kawamura Tomoteru Yamasaki Joji Yui Akiko Hatori Masanao Ogawa Yuichiro Yoshida Nobuki Nengaki Jun Maeda Ming-Rong Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1565-1568
Two novel triaryl ligands 2 and 5 with potent in vitro binding affinities for the cannabinoid subtype-2 (CB2) receptor were labeled with a positron-emitting radioactive nuclide 11C. Radioligands [11C]2, [11C]5, and their analogs [11C]3 and [11C]4 were synthesized by O-[11C]methylation of their corresponding phenol precursors with [11C]CH3I. [11C]2–5 had relatively high uptakes (>1.2% injected dose/g tissue) in mouse brains. 相似文献
16.
Alejandro Yam-Puc Leticia Chee-González Fabiola Escalante-Erosa Athimoolam Arunachalampillai Ola F. Wendt Olov Sterner Gregorio Godoy-Hernández Luis Manuel Peña-Rodríguez 《Phytochemistry letters》2012,5(1):45-48
Two pregnane derivatives (1 and 2) were isolated from the methanolic root extract of Pentalinon andrieuxii, a plant used commonly in Yucatecan traditional medicine to treat leishmaniasis. The structures of both metabolites were established using spectroscopic methods and chemical correlation reactions. An X-ray structure of 1 is reported. 相似文献
17.
Chang-Yun Wang An-Na Chen Chang-Lun Shao Liang Li Ying Xu Pei-Yuan Qian 《Biochemical Systematics and Ecology》2011,39(4-6):853-856
Chemical investigation on soft coral Sarcophyton infundibuliforme collected from the South China Sea led to the isolation and identification of 14 secondary metabolites, including ten cembrene diterpenoids (1–10), one α-tocopheryl quinone derivative (11), one prostaglandin (12), one lipid (13) and one carotinoid (14). Their structures were determined by extensive analysis of their spectroscopic data. All of these metabolites were isolated from this species for the first time. Diterpenoids 1, 2, 7 and 10 showed potent antifouling activity against the larval settlement of barnacle Balanus amphitrite. 相似文献
18.
Shuwen He Zhong Lai Qingmei Hong Jackie Shang Mikhail Reibarkh Jeffrey T. Kuethe Jian Liu Deodial Guiadeen Arto D. Krikorian Timothy A. Cernak Kevin D. Dykstra Donald M. Sperbeck Zhicai Wu Yang Yu Ginger X. Yang Tianying Jian Andreas Verras Lisa M. Sonatore Robert J. DeVita 《Bioorganic & medicinal chemistry letters》2019,29(10):1182-1186
Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study. 相似文献
19.
Santosh Kumar Avinash Tiwari S.N. Suryawanshi Monika Mittal Preeti Vishwakarma Suman Gupta 《Bioorganic & medicinal chemistry letters》2012,22(21):6728-6730
A new series of aryl substituted ketene dithioacetals 6a–h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Two compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values 3.56 and 5.12 μM and were found promising as compared with reference drug, miltefosine. On the basis of good Selectivity Indices (S.I.), they were further tested for their in vivo response against L. donovani/hamster model and showed significant inhibition of parasite multiplication 78% and 83%, respectively. These compounds were better than the existing antileishmanials in respect to IC50 and SI values, but were less active than miltefosine in vivo. 相似文献
20.
Tenvermectins (TVMs) belongs to the 16-membered macrolactone family antibiotics with attractive insecticidal properties. In order to discover more potent TVM derivatives, microbial transformation of TVM-A and TVM-B by Penicilium griseofulvum CICC 40293 and Bacillus subtilis ATCC 6633 were investigated and offered us six new metabolites (1-5, 7) with regioselectivity, especially rare glycosuccinylated products, in addition to two known compounds (6, 8). Their chemical structures were well characterized via HR-ESI-MS and 1D/2D NMR spectra. All these metabolites exhibited good acaricidal and nematicidal activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus. These results indicated that the metabolites 1-8 can serve as potential leads for future development of new insecticides. 相似文献