Abstract：
:In this study we describe an extension of our previous studies on cis-benzylidenemalononitrile tyrphostins. We have introduced S-aryl substituents in the 5 position (meta vis-a-vis the malononitrile moiety). We find that these compounds are potent blockers of EGFR kinase and its homolog HER-2 kinase. Interestingly, we find that certain S-aryltryphostins discriminate between EGFR and HER-2 kinase in favor of the HER-2 kinase domain by almost 2 orders of magnitude. When examined in intact cells it was found that these selective S-aryltrphostins are equipotent in inhibiting EGF dependent proliferation of NIH 3T3 harboring either the EGF receptor or the chimera EGF/neu (HER1-2). These findings suggest that the antiproliferative activity of these tyrphostins is mainly due to the inhibition of a mitogenic signaling element downstream to the growth receptor kinase.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gazit A,Osherov N,Posner I,Bar-Sinai A,Gilon C,Levitzki Adoi
10.1021/jm00075a010subject
Has Abstractpub_date
1993-11-12 00:00:00pages
3556-64issue
23eissn
0022-2623issn
1520-4804journal_volume
36pub_type
杂志文章abstract：:Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00736
更新日期：2017-12-14 00:00:00
abstract：:A rapid, efficient procedure useful for the radiosynthesis of [Me-3H]-MPDP+ ([methyl-3H]-4-phenyl-2,3-dihydropyridinium species) is described. Hog liver microsomes or the highly purified flavin-containing monooxygenase from hog liver quantitatively biotransforms [Me-3H]-MPTP to its corresponding radiolabeled N-oxide. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00401a032
更新日期：1988-06-01 00:00:00
abstract：:The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MR...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990191k
更新日期：1999-10-07 00:00:00
abstract：:Chemical probes are small molecules designed to bind to a specific protein and disrupt the proteins function. Although many inhibitors are reported for human carbonic anhydrase (CA) enzymes, few may be considered useful as chemical probes as they exhibit broad action against the 12 catalytically active CA isozymes. In...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01228
更新日期：2015-09-24 00:00:00
abstract：:P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9018542
更新日期：2010-03-25 00:00:00
abstract：:A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine resid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00120a006
更新日期：1988-12-01 00:00:00
abstract：:(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900426g
更新日期：2009-12-10 00:00:00
abstract：:Developing methods to incorporate protein flexibility into structure-based drug design is an important challenge. Our approach uses multiple protein structures (MPS) to create a receptor-based pharmacophore model of the desired target. We have previously demonstrated the success of the method by applying it to human i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050755m
更新日期：2006-06-15 00:00:00
abstract：:As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10-17, named Fuplatin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00128
更新日期：2019-05-09 00:00:00
abstract：:A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0208018
更新日期：2002-06-20 00:00:00
abstract：:Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01238
更新日期：2019-11-14 00:00:00
abstract：:A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineopla...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000045a
更新日期：2000-07-13 00:00:00
abstract：:A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100884b
更新日期：2010-10-28 00:00:00
abstract：:125I-labeled (E)-18-iodo-17-octadecenoic acid (13) has been prepared and evaluated in rats to determine the myocardial uptake and retention and degree of in vivo deiodination of this model iodovinyl-substituted fatty acid, which contains no structural perturbation to inhibit metabolism. This new agent was prepared by ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00367a021
更新日期：1984-01-01 00:00:00
abstract：:This paper describes the synthesis and biological evaluation of a new class of peptidomimetic falcipain-2 inhibitors based on a 1,4-benzodiazepine scaffold combined with various alpha,beta-unsaturated electrophilic functions such as vinyl-ketone, -amide, -ester, and -nitrile. The profile of reactivity of this class of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900047j
更新日期：2009-04-09 00:00:00
abstract：:A new family of chelating agents based on 4-(substituted-carbamoyl)-3-hydroxy-2-pyridinones is reported. These have optional terminal substituents on the nitrogens, and the hydroxypyridonate (HOPO) rings are attached to molecular backbones through amide linkages. A very important feature of the methyl-substituted liga...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00014a013
更新日期：1995-07-07 00:00:00
abstract：:The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01511
更新日期：2016-02-25 00:00:00
abstract：:Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.8b00370
更新日期：2018-09-27 00:00:00
abstract：:The effect of a variety of aryl substituents on the potency and selectivity of 19 analogues of 1,3-dipropyl-8-phenylxanthine as antagonists at A1- and A2-adenosine receptors in brain tissue was determined. The 4-sulfamoylphenyl and 4-carbamoylphenyl analogues are potent and somewhat selective for the A1 receptor. None...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00158a034
更新日期：1986-08-01 00:00:00
abstract：:We have determined an X-ray crystal structure for the N-methyl iodide derivative of the nonsteroidal contraceptive centchroman. The pendant aromatic substituents on C-3 and C-4 of the chroman system are nearly perpendicular to the plane of the chroman system, an orientation expected in such a chroman, but perturbed to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00031a020
更新日期：1994-03-04 00:00:00
abstract：:A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00089a023
更新日期：1992-05-29 00:00:00
abstract：:To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood-brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide-fallypride fusion molecules as model systems and determined their bind...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5004123
更新日期：2014-05-22 00:00:00
abstract：:New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaf...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800113p
更新日期：2008-09-11 00:00:00
abstract：:Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01704
更新日期：2018-04-12 00:00:00
abstract：:A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structur...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00130a022
更新日期：1989-10-01 00:00:00
abstract：:Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5013984
更新日期：2015-01-08 00:00:00
abstract：:It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00107
更新日期：2018-04-26 00:00:00
abstract：:The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the va...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b01575
更新日期：2017-07-13 00:00:00
abstract：:[4-Threonine, 7-glycine]oxytocin and [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin) were synthesized by a combination of solid-phase and classical methods of peptide synthesis. A protected octapeptide was synthesized by the solid-phase method and following ammo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00211a025
更新日期：1977-01-01 00:00:00
abstract：:The synthesis and structure-activity relationships of C-terminal octapeptide analogues of anaphylatoxin C5a have been studied. The introduction of hydrophobic amino acids into the N-acetylated native octapeptide (N-Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) (1) has led to an analogue with 100 times more activity than the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00080a004
更新日期：1992-01-24 00:00:00
