Abstract:
:Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Meier C,Knispel T,Marquez VE,Siddiqui MA,De Clercq E,Balzarini Jdoi
10.1021/jm981097rkeywords:
subject
Has Abstractpub_date
1999-05-06 00:00:00pages
1615-24issue
9eissn
0022-2623issn
1520-4804pii
jm981097rjournal_volume
42pub_type
杂志文章abstract::The syntheses of 2-amino-N-(2-benzoyl)-4-chlorophenyl)acetamides are reported. The pharmacological properties of these compounds were compared with data obtained from the corresponding cyclized products [5-(2,6-dichlorophenyl)-1,4-benzodiazepin-2-ones]. Evidence is presented which suggests that the central nervous sys...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00351a009
更新日期:1982-09-01 00:00:00
abstract::Alpha-galactoglycosphingolipids (alpha-GalGSLs) are unique immunostimulatory glycosphingolipids from marine sponges. Analysis of the glycosphingolipid composition of the marine sponge Axinella damicornis revealed the presence of a new alpha-GalGSL, damicoside (3a), which is the first alpha-GalGSL with a glycosylated g...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050506y
更新日期:2005-11-17 00:00:00
abstract::The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00172a025
更新日期:1990-10-01 00:00:00
abstract::5-(2,2-Difluorovinyl)uracil (IV) was synthesized from 2,4-dimethoxy-5-bromopyrimidine by sequential formylation, difluoromethylenation, and removal of the 2- and 4-methyl groups. Condensation of the trimethylsilyl derivative of IV with protected D-erythro-pentofuranosyl chloride followed by separation of anomers and d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00391a036
更新日期:1987-08-01 00:00:00
abstract::To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essent...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060736s
更新日期:2006-11-02 00:00:00
abstract::To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00585
更新日期:2017-07-27 00:00:00
abstract::Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a very promiscuous transporter. Herein we used topological polar surface area (TPSA), a descriptor defined as the sum of surfaces of polar atoms in a molecule, to analyze drug transport by MRP1. We suggested that compounds with high TPSA are transported while t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801389m
更新日期:2009-02-26 00:00:00
abstract::Serotonin (5-HT) binds with nearly identical affinity at the various central 5-HT binding sites. Few agents bind with selectivity for 5-HT1A sites. The beta-adrenergic antagonist propranolol binds stereoselectively both at 5-HT1A and 5-HT1B sites (with a several-fold selectivity for the latter) and, whereas it is a 5-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00124a021
更新日期:1989-04-01 00:00:00
abstract::Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0304414
更新日期:2003-12-18 00:00:00
abstract::Water-ligand observed via gradient spectroscopy (WaterLOGSY) represents a powerful method for primary NMR screening in the identification of compounds interacting with macromolecules, including proteins and DNA or RNA fragments. The method is useful for the detection of compounds binding to a receptor with binding aff...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm011122k
更新日期:2002-06-06 00:00:00
abstract::The maximum achievable accuracy of in silico models depends on the quality of the experimental data. Consequently, experimental uncertainty defines a natural upper limit to the predictive performance possible. Models that yield errors smaller than the experimental uncertainty are necessarily overtrained. A reliable es...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300131x
更新日期:2012-06-14 00:00:00
abstract::Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel F...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00140
更新日期:2015-06-11 00:00:00
abstract::The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, e...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm991129q
更新日期:2000-04-06 00:00:00
abstract::A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000375v
更新日期:2001-02-15 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::Three N-C8-bridged analogues 4-6 of the opiate etorphine (3) were synthesized and evaluated for opiate agonism and antagonism. In each case ring closure was effected by intramolecular N-alkylation with a suitably developed C8 side chain. Another key synthetic step was the selective monoprotection of diol 11, which all...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00394a016
更新日期:1987-11-01 00:00:00
abstract::Collective experience in structure-based lead progression has found electrostatic interactions to be more difficult to optimize than shape-based ones. A major reason for this is that the net electrostatic contribution observed includes a significant nonintuitive desolvation component in addition to the more intuitive ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm051105l
更新日期:2006-04-20 00:00:00
abstract::Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01395
更新日期:2017-11-09 00:00:00
abstract::Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c01290
更新日期:2020-11-25 00:00:00
abstract::Over 25 selected naphthalenesulfonic acid derivatives were evaluated for their inhibitory effect on two different functional domains of the HIV-1 reverse transcriptase (RT), namely the ribonuclease H and DNA polymerase activities. Most of the analogues were found to be either specific toward the DNA polymerase activit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00042a004
更新日期:1994-08-05 00:00:00
abstract::A new structurally distinct class of 14-membered-ring macrolides is characterized by a keto-function instead of the cladinose sugar, well-known for its fragility even in weakly acidic media. This new class called ketolides is endowed with remarkable antibacterial activity against macrolide-resistant strains. A complet...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970852i
更新日期:1998-08-27 00:00:00
abstract::The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01679
更新日期:2016-04-14 00:00:00
abstract::5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisome...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01547
更新日期:2020-03-12 00:00:00
abstract::The four stereoisomers of the muscarinic agonist 7 have been synthesized from enantiomerically pure exo-azanorbornane esters (13a,b). The esters were obtained in optically active form by separation of the carboxamide diastereomers 12a,b, formed from the borane complex of exo-azanorbornane-3-carboxylate 10 and a chiral...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00083a016
更新日期:1992-03-06 00:00:00
abstract::Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01507
更新日期:2017-03-09 00:00:00
abstract::The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray cry...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00155a006
更新日期:1986-05-01 00:00:00
abstract::Computational ADME (absorption, distribution, metabolism, and excretion) models may be used early in the drug discovery process in order to flag drug candidates with potentially problematic ADME profiles. We report the development, validation, and application of quantitative structure-property relationship (QSPR) mode...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020491t
更新日期:2003-07-03 00:00:00
abstract::The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00143a007
更新日期:1981-11-01 00:00:00
abstract::Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; Rx...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500797g
更新日期:2014-09-25 00:00:00
abstract::The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00115a010
更新日期:1991-11-01 00:00:00