Abstract:
:A novel, simple, and efficient method for the chemical resolution of epidithiodioxopiperazines is reported, which is based upon covalent formation of diastereomers. This method might be a general one for the resolution of chiral cyclic disulfides. Dithiol 5, prepared from 2 by reduction with NaBH4, was allowed to react with the disulfenyl chloride 8 to yield 9 and 10, which were separated by short-column chromatography on silica gel. From these, the optically pure enantiomers 11 and 12, respectively, were obtained by reduction with NaBH4, followed by reoxidation with I2-pyridine. In this way the precursor 7 of the resolving agent could also be recovered. The absolute configurations of 11 and 12 were derived from CD spectra. Kinetic asymmetric transformation of the gliotoxin analogue 2 with the diphosphine 6 gave a 19% enrichment in one enantiomer of the starting material. Surprisingly, both enantiomers were found to inhibit reverse transcriptase, the RNA-dependent DNA polymerase, to the same degree, indicating that there is no relation between this property of epidithiodioxopiperazines and their bridgehead configurations. From the X-ray crystal structure determination it can be seen that there is a considerable torsional and conformational strain in compound 2, which might enhance the ease of cleavage of the S-S bond. A possible relationship between this property and the biological activity of 2 is discussed.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Ottenheijm HC,Herscheid JD,Tijhuis MW,Nivard RJ,De Clercq E,Prick PAdoi
10.1021/jm00206a016subject
Has Abstractpub_date
1978-08-01 00:00:00pages
799-804issue
8eissn
0022-2623issn
1520-4804journal_volume
21pub_type
杂志文章abstract::We synthesized two series (7a-i and 8a-i) of 2,3,5-substituted [1,2,4]-thiadiazole analogues of SCH-202676 (7a, 2,3-diphenyl-5-N-methylimino-2H-[1,2,4]-thiadiazole) with emphasis on the N-imino substituent. Compounds 7a-g,i and 8a-g at a final concentration of 1 microM significantly inhibited [(3)H]CCPA (2-chloro-N(6)...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049337s
更新日期:2005-02-24 00:00:00
abstract::An efficient and general method has been developed for fluorine-18 labeling of beta-blockers that possess the propanolamine moiety. A new synthetically versatile intermediate, 3-(1-(benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (13), was prepared and can be conjugated to any phenoxy core....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800227h
更新日期:2008-08-28 00:00:00
abstract::MLL1 is a histone 3 lysine 4 (H3K4) methyltransferase and a promising new cancer therapeutic target. The catalytic activity of MLL1 is regulated by the formation of a core complex consisting of MLL1, WDR5, RbBP5, and Ash2L. The interaction between WDR5 and MLL1 plays an essential role in regulation of the H3K4 methylt...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100139b
更新日期:2010-07-22 00:00:00
abstract::A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the desig...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050463l
更新日期:2005-09-22 00:00:00
abstract::Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and poten...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00982
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abstract::The cesium and tetramethylammonium (TMA) salts of polyoxotungstate anions with covalently attached organosilyl groups of formula [(RSi)2O]SiW11O39(4-), where R = CH2CH2COCH3, (CH2)3CN, and CH==CH2 (1-R, cesium salt, unless otherwise noted) have been prepared, purified, and spectroscopically characterized. The water so...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00085a008
更新日期:1992-04-03 00:00:00
abstract::Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtaine...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm7015599
更新日期:2008-09-11 00:00:00
abstract::A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00380a020
更新日期:1985-02-01 00:00:00
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journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01937
更新日期:2020-05-14 00:00:00
abstract::1-Aroylindoline, 1-aroyl-1,2,3,4-tetrahydroquinoline, and 1-aroylindole derivatives were synthesized and evaluated for anticancer activity. The 4-amino and 4-hydroxy-1-aroylindoles 26 and 27 with IC 50 of 0.9 and 0.6 microM, respectively, exhibited antitubulin activity superior or comparable to that of colchicine and ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800150d
更新日期:2008-07-24 00:00:00
abstract::The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is pr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060887v
更新日期:2007-09-06 00:00:00
abstract::Isoform-selective antagonists of the lysophosphatidic acid (LPA) G-protein coupled receptors (GPCRs) have important potential uses in cell biology and clinical applications. Novel phosphonothioate and fluoromethylene phosphonate analogues of carbacyclic phosphatidic acid (ccPA) were prepared by chemical synthesis. The...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060351+
更新日期:2006-08-24 00:00:00
abstract::5'-Deoxy-5-fluorouridine (5'-dFUrd, 1) possesses a significantly higher chemotherapeutic index than other fluoropyrimidines as a result of its being selectivity cleaved in tumors to 5-fluorouracil (FUra) by uridine phosphorylase. Because 1 is a relatively poor substrate for this enzyme, we synthesized a series of 5'-d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00350a024
更新日期:1982-08-01 00:00:00
abstract::A series of phenylenebis(oxy)bis[2,2-dimethylpentanoic acid]s have been synthesized and evaluated as potential hypolipidemic agents. Compound 18 (CI-924) was found to be the most potent compound in this series. In rats, compound 18 not only reduced low-density lipoprotein cholesterol but also increased high-density li...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00361a015
更新日期:1983-07-01 00:00:00
abstract::On-line affinity capillary electrophoresis-electrospray ionization-mass spectrometry (ACE-MS) was used for the simultaneous measurement of multiple binding constants of an all-D-tetrapeptide library to the model receptor, vancomycin. Determination of Kd values for the 19 peptides of the form Fmoc-DXYA is demonstrated....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970578s
更新日期:1998-03-26 00:00:00
abstract::We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0499211
更新日期:2004-09-23 00:00:00
abstract::Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzim...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00036a017
更新日期:1994-05-13 00:00:00
abstract::A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptos...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00064a005
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abstract::A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, follo...
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pub_type: 杂志文章
doi:10.1021/jm00053a007
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abstract::Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution...
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更新日期:2006-10-19 00:00:00
abstract::Novel tumor-targeting theranostic conjugates 1 and 2, bearing either a fluorine-labeled prosthetic as a potential (18)F-PET radiotracer (1) or a fluorescence probe (2) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of 2 in biotin-receptor positive (BR+) canc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2015-03-12 00:00:00
abstract::A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guano...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9911231
更新日期:2000-01-27 00:00:00
abstract::3,4-Dihydro-2(1H)-quinolones, evolved from 2-carboxy-1,2,3,4,- tetrahydroquinolines and 3-carboxy-4-hydroxy-2(1H)-quinolones, have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA receptor and for AMPA [(RS)-alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid] antag...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00074a021
更新日期:1993-10-29 00:00:00
abstract::We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximatel...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2007-02-22 00:00:00
abstract::In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:1996-01-19 00:00:00
abstract::Drug-resistant bacterial infections and lack of available antibacterial agents in clinical practice are becoming serious risks to public health. We synthesized a new class of haloemodins by modifying a traditional Chinese medicine component, emodin. The novel haloemodin exerts strong inhibitory activity on bacterial t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2014-05-08 00:00:00
abstract::The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) binds to human A3 receptors with high affinity (Ki = 14 nM), while it lacks affinity at rat A3 receptors. Acylated derivatives of the 5-amino group and other modifications were prepared in an effort to provide A3 subtype...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960482i
更新日期:1996-10-11 00:00:00
abstract::Proton magnetic spectra have been recorded for muscarine and two biologically active cyclopentane analogues. In order to observe homonuclear intramolecular nuclear Overhauser effects, the -N+(CH3)3 signal was irradiated and increases in integrated intensities for other key signals in the molecule were observed. The re...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00205a028
更新日期:1978-07-01 00:00:00
abstract::We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had com...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01204
更新日期:2016-11-23 00:00:00
abstract::The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, con...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
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更新日期:2012-03-22 00:00:00