Abstract：
:We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki approximately 300 nM) despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Basse N,Piguel S,Papapostolou D,Ferrier-Berthelot A,Richy N,Pagano M,Sarthou P,Sobczak-Thépot J,Reboud-Ravaux M,Vidal Jdoi
10.1021/jm0701324subject
Has Abstractpub_date
2007-06-14 00:00:00pages
2842-50issue
12eissn
0022-2623issn
1520-4804journal_volume
50pub_type
杂志文章abstract：:Carbonic anhydrase inhibitors are effective in lowering intraocular pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help regulate fluid secretion into the anterior chamber of the eye. Because inhibitors currently formulated as...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010163d
更新日期：2002-02-14 00:00:00
abstract：:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm058261c
更新日期：2005-12-29 00:00:00
abstract：:6-Chloropurine derivatives of gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 3a, gamma-(Z)-ethylidene-2-methoxy-3-(4-nitro)benzyloxybutenolide 3b, gamma-(Z)-ethylidene-2-(4-nitro)benzyloxy-3-methoxybutenolide 3c, gamma-(Z)-ethylidene-2,3-di(4-nitro)benzyloxybutenolide 3d, and dimethylphosphono-gamma-(Z)-ethylidene-2,3-d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0004446
更新日期：2001-05-24 00:00:00
abstract：:The noradrenergic neurotransmitter (-)-norepinephrine (1) is very easily oxidized at physiological pH to an o-quinone (2) that normally cyclizes and subsequently oxidatively polymerizes to black melanin. In this investigation it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by efficiently scave...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960016t
更新日期：1996-05-10 00:00:00
abstract：:Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogena...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a035
更新日期：1990-01-01 00:00:00
abstract：:The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00442
更新日期：2016-11-10 00:00:00
abstract：:Lymphatic filariasis (elephantiasis) is a global public health problem caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. We have previously reported anthraquinones from daylily roots with potent activity against pathogenic trematode Schistosoma mansoni. Here we report the synthesis of novel ant...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492655
更新日期：2005-04-21 00:00:00
abstract：:Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-molecule inhibitors of oncogenic t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800791f
更新日期：2009-02-26 00:00:00
abstract：:1,3-Dipolar cycloaddition of benzyl azide or peracetylated glucopyranosyl azides to propargyl halides or 1,4-dihalobutynes yielded 1-benzyl- or 1-glycosyl(halomethyl)-1,2,3-triazoles. Alkylating chloromethyl- bromomethyl- and iodomethyl-1,2,3-triazoles were also obtained from the corresponding hydroxymethyl derivative...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00191a007
更新日期：1979-05-01 00:00:00
abstract：:Multiple recent studies have focused on unraveling the content of the medicinal chemist's toolbox. Here, we present an investigation of chemical reactions and molecules retrieved from U.S. patents over the past 40 years (1976-2015). We used a sophisticated text-mining pipeline to extract 1.15 million unique whole reac...
journal_title：Journal of medicinal chemistry
pub_type： 历史文章,杂志文章
doi：10.1021/acs.jmedchem.6b00153
更新日期：2016-05-12 00:00:00
abstract：:A series of cis and trans bicyclic lactones was prepared as congeners of podophyllotoxin (1) and evaluated as antimitotic agents both in cell cultures grown in vitro and in an in vitro protein binding assay. All compounds displayed insignificant activity-a result which may reflect insufficient structural similarity to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00223a025
更新日期：1976-01-01 00:00:00
abstract：:We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (-)-Δ(8)-THC analogues encompassing a carboxye...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501165d
更新日期：2015-01-22 00:00:00
abstract：:Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes. Although a large number of PAINS have been classified, often on the basis of individual studies or chemical experience, little has been done s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00154
更新日期：2017-05-11 00:00:00
abstract：:A combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301112z
更新日期：2012-12-13 00:00:00
abstract：:The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00124a018
更新日期：1989-04-01 00:00:00
abstract：:Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9700981
更新日期：1997-10-10 00:00:00
abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01888
更新日期：2020-09-24 00:00:00
abstract：:Short peptide-based inhibition of fusion remains an attractive goal in antihuman immunodeficiency virus (HIV) research based on its potential for the development of technically and economically desirable antiviral agents. Herein, we report the use of the dithiol bisalkylation reaction to generate a series of m-xylene ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00882
更新日期：2019-10-10 00:00:00
abstract：:Four hybrid antibiotics combining structural features of chloramphenicol (1a), sparsomycin (2b), lincomycin (5c), and puromycin (6d)--lincophenicol (1c), chloramlincomycin (5a), sparsolincomycin (5b), and sparsopuromycin (6b)--were synthesized. They were investigated as inhibitors of several partial reactions of proca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00061a015
更新日期：1993-04-30 00:00:00
abstract：:Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701049p
更新日期：2008-01-10 00:00:00
abstract：:Four highly charged, water soluble platinum-acridine bisintercalating agents have been synthesized. Depending on the cis/trans isomerism of the metal and the nature of the acridine side chains, bisintercalation induces/stabilizes the classical Watson-Crick B-form or a non-B-form. Circular dichroism spectra and chemica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8003569
更新日期：2008-06-12 00:00:00
abstract：:A short series of the title compounds was prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. All but the two N-methylated derivatives were active in this screen by the intravenous route, the most potent being the symmetrical dimethyl compound, 4,9-dihydro-6,7-dimethyl-4,9...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00359a016
更新日期：1983-05-01 00:00:00
abstract：:Several substance P analogues containing various D-amino acid modifications have been synthesized by the solid-phase procedure, detached from the solid support by ammonolysis, and purified by gel filtration combined with reversed-phase chromatography. Three compounds were fair to very potent competitive antagonists of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00353a008
更新日期：1982-11-01 00:00:00
abstract：:A series of 7 alpha-methoxy-7 beta-amido-3-chloro-3-cephem-4-carboxylic acids was prepared and evaluated for biological activity. When compared with the parent 7-non-methoxy analogues, these new 7 alpha-methoxy-3-chloro cephalosporins displayed diminished antimicrobial activity. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00118a024
更新日期：1988-10-01 00:00:00
abstract：:The perceived and actual burden of false positives in high-throughput screening has received considerable attention; however, few studies exist on the contributions of distinct mechanisms of nonspecific effects like chemical reactivity, assay signal interference, and colloidal aggregation. Here, we analyze the outcome...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901070c
更新日期：2010-01-14 00:00:00
abstract：:The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01784
更新日期：2020-04-23 00:00:00
abstract：:Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs. These compounds were obtained by a condensation reaction of 4-chloro-1H-pyrazolo[3,4-b]pyridine with several aniline derivatives. Some of them were also obtained by a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0401006
更新日期：2004-10-21 00:00:00
abstract：:We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0302344
更新日期：2003-11-20 00:00:00
abstract：:An application of the neural network to quantitative structure-activity relationship (QSAR) analysis has been studied. The new method was compared with the linear multiregression analysis in various ways. It was found that the neural network can be a potential tool in the routine work of QSAR analysis. The mathematica...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm00171a037
更新日期：1990-09-01 00:00:00
abstract：:A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a061
更新日期：1990-01-01 00:00:00
