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1.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(9):789-799
[14C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [14C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐14C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐13C4]‐ethyl acetoacetate and [D4]‐methanol in six steps in an overall yield of 2%. [13C4]‐2‐methylnicotic acid, was prepared by condensation of [13C4]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
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S. Ballet A. Frycia J. Piron N.N. Chung P.W. Schiller P. Kosson A.W. Lipkowski D. Tourw 《Chemical biology & drug design》2005,66(5):222-230
Abstract: The synthesis of conformationally restricted dipeptidic moieties 4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Aba)‐Gly ([(4S)‐amino‐3‐oxo‐1,2,4,5‐tetrahydro‐1H‐2‐benzazepin‐2‐yl]‐acetic acid) and 8‐hydroxy‐4‐amino‐1,2,4,5‐tetrahydro‐2‐benzazepin‐3‐one (Hba)‐d ‐Ala ([(4S)‐amino‐8‐hydroxy‐3‐oxo‐1,2,4,5‐tetrahydro‐benzo[c]azepin‐2‐yl]‐propionic acid) was based on a synthetic strategy that uses an oxazolidinone as an N‐acyliminium precursor. Introducing these Aba scaffolds into the N‐terminal tetrapeptide of dermorphin (H‐Tyr‐d ‐Ala‐Phe‐Gly‐Tyr‐Pro‐Ser‐NH2)‐induced remarkable shifts in affinity and selectivity towards the opioid μ‐ and δ‐receptors. This paper provides the synthesis and biological in vitro and in vivo evaluation of constricted analogues of the N‐terminal tetrapeptide H‐Tyr‐d ‐Ala‐Phe‐Gly‐NH2, which is the minimal subunit of dermorphin needed for dermorphin‐like opiate activity. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2005,48(5):323-330
2‐[14C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [14C]‐PS‐1145) was synthesized from [14C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[14C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [14C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd. 相似文献
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Improving the Specificity of the Prostate‐Specific Antigen Substrate Glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln as a Promoiety 下载免费PDF全文
To develop PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln, systematic replacements of the N‐terminal segment with D‐retro‐inverso‐peptides were performed with the incorporation of 7‐amino‐4‐methylcoumarin (7‐AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. The D‐retro‐inverso‐peptide conjugates with P2‐P5 D‐amino acid substitutions were moderate but poorer PSA substrates as compared to the original peptide, suggesting that inversion of the amide bonds and/or incorporation of the additional atom as in the urea linker adversely affected PSA binding. However, P5 substitution of Hyp with Ser showed significant improvements in PSA cleavage rate; the resulting AMC conjugate, glutaryl‐Ser‐Ala‐Ser‐Chg‐Gln‐AMC ( 11 ), exhibited the fastest PSA cleavage rate of 351 pmol/min/100 nmol PSA. In addition, GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC (conjugate 6 ) was the second best PSA substrate and released 7‐AMC at a rate of 225 pmol/min/100 nmol PSA as compared to 171 pmol/min/100 nmol PSA for the control conjugate glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln‐AMC. Incubations of selected AMC conjugates with mouse and human plasma revealed that GABA←D‐Ser‐ψ[NH‐CO‐NH]‐Ala‐Ser‐Chg‐Gln‐AMC ( 5 ) and GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC ( 6 ) were most stable to non‐PSA‐mediated proteolysis. Our results suggest that the PSA specificity of glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln is improved with Ser and mGly substitutions of Hyp at the P5. 相似文献
6.
Qiong‐You Wu Li‐Li Jiang Yang Zuo Zhi‐Fang Wang Zhen Xi Guang‐Fu Yang 《Chemical biology & drug design》2014,84(4):431-442
Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, 1H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with Ki value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2002,45(2):107-113
Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐14C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[14C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
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γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐14C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2005,48(8):621-627
N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐13C4‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐13C4 by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐13C4. This pyrrole analogue underwent a Vilsmeyer acylation with POCl3/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom 13C. By using DMF [α‐14C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd. 相似文献
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Efficient Synthesis of Novel 3‐Aryl‐5‐(4‐chloro‐2‐morpholinothiazol‐5‐yl)‐4,5‐dihydro‐1H‐pyrazoles and Their Antifungal Activity Alone and in Combination with Commercial Antifungal Agents 下载免费PDF全文
Juan Ramírez María Victoria Rodríguez Jairo Quiroga Rodrigo Abonia Maximiliano Sortino Susana A. Zacchino Braulio Insuasty 《Archiv der Pharmazie》2014,347(8):566-575
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Makoto Ukai Hiroko Tamoto Tomoko Tanaka Tsutomu Kameyama 《Human psychopharmacology》1999,14(7):453-458
The present study was designed to characterize the dopamine D3 receptor agonist R(+)‐7‐hydroxy‐N,N‐di‐n‐propyl‐2‐aminotetralin (R(+)‐7‐OH‐DPAT)‐induced changes in locomotor activity in mice. Although R(+)‐7‐OH‐DPAT (0·01–10 mg/kg) produced a significant decrease in horizontal and vertical motility within 15 min after the start of behavioural measurements, the dopamine D1 receptor antagonist R(+)‐SCH23390 (0·05 mg/kg) and the dopamine D3 receptor antagonist (+)‐UH232 (10 mg/kg) had no antagonistic effects on the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypomotility, while the dopamine D2 receptor antagonist S(−)‐sulpiride (20 mg/kg) augmented it. Although R(+)‐7‐OH‐DPAT (0·01–1 mg/kg) had no marked effects on horizontal or vertical motility, higher doses (3 and 10 mg/kg) of the drug produced a significant increase in horizontal or vertical motility from 30 to 90 min after the start of the behavioural measurements. S(−)‐sulpiride (20 mg/kg) and (+)‐UH232 (10 mg/kg) almost completely inhibited the R(+)‐7‐OH‐DPAT (3 mg/kg)‐induced hypermotility, whereas the antagonistic effects of R(+)‐SCH23390 (0·05 mg/kg) were partial. These results suggest that the R(+)‐7‐OH‐DPAT‐induced hypermotility is mediated principally via dopamine D2 and D3 receptors, whereas it is unlikely that the hypomotility results from the activation of presynaptic dopamine D2 or D3 receptors. Copyright © 1999 John Wiley & Sons, Ltd. 相似文献
12.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(1):71-76
N‐(1‐methyl‐2‐oxo‐5‐phenyl‐2,3‐dihydro‐1H‐benzo[e][1,4]diazepin‐3‐yl)‐benzamide‐[carboxyl‐14C] has been synthesized from benzonitrile‐[cyano‐14C]. Copyright © 2005 John Wiley & Sons, Ltd. 相似文献
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D. S. Yamashita R. Xie H. Lin B. Wang S. D.‐H. Shi C. J. Quinn M. E. Hemling C. Hissong T. A. Tomaszek D. F. Veber 《Chemical biology & drug design》2004,63(3):265-269
Abstract: The design, synthesis, enzymologic, and protein mass spectrometric characterization of benzodioxocin‐3‐one and N‐acyl‐3‐amino‐3‐buten‐2‐one inhibitors of the cysteine protease cathepsin K are described. The benzodioxocin‐3‐one ring system is chemically unstable giving rise to a mixture of N‐acyl‐3‐amino‐3‐buten‐2‐one and hemiketals. This mixture of N‐acyl‐3‐amino‐3‐buten‐2‐one and hemiketals potently inhibits recombinant, human cathepsin K (IC50 = 36 nM) by a time‐independent, irreversible mechanism. Formation of a covalent adduct between cathepsin K and inhibitor has been confirmed by mass spectrometry. 相似文献
15.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(8):699-705
We report here a facile synthesis of (RS) methyl‐2‐([2′‐14C]4,6‐dimethoxypyrimidin‐2′‐yloxy)‐2‐phenyl [1‐14C]ethanoate under microwave irradiation. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
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Amit Goel Farhan Jalees Ahmad Raman Mohan Singh Gyanendra Nath Singh 《The Journal of pharmacy and pharmacology》2010,62(2):273-278
Objectives The aim of this study was to develop 3‐acetyl‐11‐keto‐β‐boswellic acid (AKBA)‐loaded polymeric nanomicelles for topical anti‐inflammatory and anti‐arthritic activity. Methods Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N‐isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In‐vitro and in‐vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti‐inflammatory and anti‐arthritic activity. Key findings TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In‐vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti‐inflammatory and anti‐arthritic activity compared with the AKBA gel. Conclusions This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti‐inflammatory and anti‐arthritic activity. 相似文献
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Synthesis of N‐(2‐diethylamino‐ethyl)‐4‐(4‐fluoro‐benzamido)‐2‐methoxybenzamide (desiodo‐MIP‐1145) by coupling technique and its radioiodination: a potential melanoma imaging agent 下载免费PDF全文
H. Aglan S. A. Kandil A. F. EL‐Kafrawy U. Seddik 《Journal of labelled compounds & radiopharmaceuticals》2016,59(9):372-374
Radioiodinated MIP‐1145, which specifically targets melanin, is an ideal candidate for targeted therapy of melanoma. An analogue of MIP‐1145 lacking the iodo‐substituent (desiodo‐MIP‐1145) was synthesized as a labeling precursor in three simple steps. The radioiodination of desiodo‐MIP‐1145 by iodine‐125 was carried out via an electrophilic substitution reaction. An optimization study for the iodination reaction was carried out. The labeled compound was isolated and purified by means of electrophoresis and HPLC. The maximum radiochemical yield, 76%, was obtained with radiochemical purity greater than 99%. The log P value for [125I]MIP‐1145 was measured as 4.5. 相似文献
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Design,Synthesis, and Antitumor Activity of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones 下载免费PDF全文
Wan Li Zi‐Hui Yang Ai‐Xi Hu Xiao‐Wei Yan Na Ding Jiao Ye 《Chemical biology & drug design》2015,86(6):1339-1350
A series of (E,Z)‐1‐(dihydrobenzofuran‐5‐yl)‐3‐phenyl‐2‐(1,2,4‐triazol‐1‐yl)‐2‐propen‐1‐ones ( C1 – C35 ) were designed and synthesized, and the structures of compounds (Z)‐ C27 and (Z)‐ C29 were confirmed by single‐crystal X‐ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF‐7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)‐ C24 exhibited the most consistent potent activities against three neoplastic cells with IC50 values ranging from 3.2 to 7.1 μm . Further researches demonstrated that compounds (E,Z)‐ C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure–activity relationship between the configurations and cytotoxicity of the compounds was also investigated. 相似文献
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Fengjiun Kuo Dean K. Clodfelter Tamara R. Priest 《Journal of labelled compounds & radiopharmaceuticals》2007,50(8):706-710
Carbon‐14‐labeled 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]naphthalen‐2‐ol, a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6‐methoxy‐1‐tetralone‐[carbonyl‐14C], was synthesized from 3‐(3‐methoxyphenyl)‐propionic acid via an intra‐molecular Friedel–Crafts acylation of 4‐(3‐methoxyphenyl)butanoic acid‐[carboxy‐14C]. A palladium catalyzed alpha‐keto arylation of 6‐methoxy‐1‐tetralone with 4‐methanesulfonyl‐phenyl bromide, followed by a sequence of bromination, DDQ dehydrogenation, aryl Ullmann reaction, and demethylation with BBr3 gave the desired product LY2066948‐[14C]. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献