Abstract:
:A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6- methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed by dehydration of the resulting carbinols. The benzofurans are ligands for antiestrogen-binding sites (AEBS) and display no significant interaction with the estrogen receptor (ER). All bind to AEBS with equivalent or greater affinity than tamoxifen. These compounds decrease [3H]thymidine incorporation in AEBS-containing EL4 lymphoid cells and MCF7 breast cancer cells in a concentration-dependent manner between 10(-8) and 10(-6) M and are generally more inhibitory than tamoxifen. In contrast, they have no effect on [3H]thymidine incorporation by an AEBS-deficient variant of the MCF7 cell line, RTx6. The present findings of (1) selective and high affinity binding of the benzofurans to AEBS, (2) their concentration-dependent inhibition of [3H]thymidine incorporation in AEBS-containing cells, and (3) their lack of antiproliferative effect in an AEBS-deficient cell line suggest a functional role for AEBS in mediating the antigrowth effect of these compounds. Two of the more active benzofuran compounds also significantly inhibited de novo cholesterol biosynthesis in EL4 cells which lack ER. This effect could be obtained after 5 h of treatment and preceded significant loss of cell viability. This is the first demonstration that selective ligands of AEBS (other than the known nonsteroidal antiestrogens) interfere with cholesterol biosynthesis-an action that may contribute to their antigrowth effect.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Teo CC,Kon OL,Sim KY,Ng SCdoi
10.1021/jm00086a002keywords:
subject
Has Abstractpub_date
1992-04-17 00:00:00pages
1330-9issue
8eissn
0022-2623issn
1520-4804journal_volume
35pub_type
杂志文章abstract::The superior activity of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (MeCCNU) against advanced murine Lewis lung carcinoma in comparisons with the cis form and other nitrosoureas prompted the synthesis of a number of MeCCNU analogues, including several cis-trans pairs. The methyl group was replaced b...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00212a019
更新日期:1977-02-01 00:00:00
abstract::C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, β-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500263v
更新日期:2014-05-22 00:00:00
abstract::Novel substituted benzoyl benzoic acids and phenylacetic acids 1-14 have been synthesized and evaluated for inhibition of rat and human steroid 5alpha-reductase isozymes 1 and 2. The compounds turned out to be potent and selective human type 2 enzyme inhibitors, exhibiting IC(50) values in the nanomolar range. The phe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050728w
更新日期:2006-01-26 00:00:00
abstract::A series of 2,3-diaminopropionanilides was synthesized by acylation of mono- and disubstituted aniline derivatives with 2,3-dibromopropionyl chloride and subsequent amination with the appropriate secondary amines. The target compounds were evaluated in mice for antiarrhythmic efficacy against chloroform-induced tachyc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00141a008
更新日期:1981-09-01 00:00:00
abstract::The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding en...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00045a022
更新日期:1994-09-16 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::2-Alkylchromen-4-one 6-O-sulfamates, a new class of potent steroid sulfatase (STS) inhibitors, were evaluated for their estrogenic potential. Structure-activity relationships for estrogenic activity were identified; however, no correlation with STS inhibition was found. Estrogenicity is favored by bulky side chains an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030926s
更新日期:2003-11-06 00:00:00
abstract::Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformati...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00053a001
更新日期:1993-01-08 00:00:00
abstract::HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of contin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801201u
更新日期:2009-02-12 00:00:00
abstract::In a previous study, a cocrystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01340
更新日期:2016-11-23 00:00:00
abstract::Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to no...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.0c00021
更新日期:2020-05-28 00:00:00
abstract::A diverse 5000-compound library was synthesized from commercially available diamines and screened for activity against Mycobacterium tuberculosis in vitro, revealing 143 hits with minimum inhibitory concentration (MIC) equal to or less than 12.5 microM. New prospective scaffolds with antitubercular activity derived fr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050948+
更新日期:2006-06-01 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::2-, 6-, And 8-alkylated (methyl, ethyl, and vinyl) adenosine analogues were synthesized by a palladium-catalyzed cross-coupling of a tetraalkyltin with the halogenated purine nucleosides. The synthesis of the 8-substituted analogues was accomplished using a transient protection procedure. The 6-alkylated-9-beta-D-ribo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00072a013
更新日期:1993-10-01 00:00:00
abstract::A variety of nitroheterocyclic carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug ther...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030308b
更新日期:2003-12-04 00:00:00
abstract::G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs....
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,随机对照试验
doi:10.1021/jm2010964
更新日期:2012-04-26 00:00:00
abstract::This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discove...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9000242
更新日期:2009-05-14 00:00:00
abstract::Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimeth...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900865m
更新日期:2010-01-14 00:00:00
abstract::A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00125a003
更新日期:1989-05-01 00:00:00
abstract::The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in anima...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01373
更新日期:2016-12-08 00:00:00
abstract::Deregulation of CK1 (casein kinase 1) activity can be involved in the development of several pathological disorders and diseases such as cancer. Therefore, research interest in identifying potent CK1-specific inhibitors is still increasing. A previously published potent and selective benzimidazole-derived CK1δ/ε-speci...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm500600b
更新日期:2014-10-09 00:00:00
abstract::In a search for improved multiple drug resistance (MDR) modulators, we identified a novel series of substituted pyrroloquinolines that selectively inhibits the function of P-glycoprotein (Pgp) without modulating multidrug resistance-related protein 1 (MRP1). These compounds were evaluated for their toxicity toward dru...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0303204
更新日期:2004-03-11 00:00:00
abstract::Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclic WXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one d-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00163
更新日期:2017-06-22 00:00:00
abstract::Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI ri...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.0c00524
更新日期:2020-10-22 00:00:00
abstract::A series of neutral, lipophilic 99mTc mixed-ligand complexes of the general formula 99mTcOL1L2, where L1H2 is an N-substituted bis-(2-mercaptoethyl)amine, [X-CH2CH2N(CH2CH2SH)2], [SNS], and L2H is a monodentate thiol (RSH), [S], has been synthesized and evaluated in rodents for potential use in brain blood flow imagin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960273y
更新日期:1997-08-01 00:00:00
abstract::Although the illness malaria is caused by the asexual blood stages, the presence of gametocytes is directly responsible for the infection of the vector Anopheles, thus perpetuating the plasmodial cycle. Fight against malaria is more than ever a current problem, and the solution will probably go through the development...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm3005898
更新日期:2012-12-13 00:00:00
abstract::The coupling of two different pharmacophores, each endowed with different biological properties, afforded the hybrid compound lipocrine (7), whose biological profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compound that inhibits the catalytic activity of AC...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049112h
更新日期:2005-01-27 00:00:00
abstract::In a small range finding study a number of N-benzylpiperazino derivates of 3-nitro-4-hydroxycoumarin have been shown to combine potent H1-antihistamine activity with that of mast cell stabilization as demonstrated by their activity as antagonists of histamine on guinea pig ileum and by their inhibition of the release ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00377a013
更新日期:1984-11-01 00:00:00
abstract::We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not in...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901126m
更新日期:2009-11-12 00:00:00
abstract::Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicoc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00857
更新日期:2015-11-25 00:00:00