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 scavenging o-quinone 2 to give, initially, 5-S-cysteinylnorepinephrine (6) and 2-S-cysteinylnorepinephrine (7). These cysteinyl conjugates are appreciably more easily oxidized than 1 to o-quinones that, in part, are further attacked by CySH to give 2,5-bi-S-cysteinylnorepinephrine (8), an even more easily oxidized compound. The o-quinone intermediates formed upon oxidation of 6-8 can also undergo facile intramolecular cyclizations to bicyclic o-quinone imines that oxidize the cysteinyl conjugates from which they are derived in a reaction sequence that leads initially to a number of dihydrobenzothiazines. At least two of these compounds, 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5- hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (9) and 8-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (10) are lethal when administered into the brains of mice. The in vitro chemical pathways elucidated in this investigation might be of relevance to the depigmentation and degeneration of neuromelanin-pigmented noradrenergic cell bodies in the locus ceruleus in Parkinson's Disease and to the degeneration of noradrenergic nerve terminals in Alzheimer's Disease and following transient cerebral ischemia (stroke).
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Shen XM,Dryhurst Gdoi
10.1021/jm960016tsubject
Has Abstractpub_date
1996-05-10 00:00:00pages
2018-29issue
10eissn
0022-2623issn
1520-4804pii
jm960016tjournal_volume
39pub_type
杂志文章abstract：:Several new 1-substituted 3,5-dimethylpyrazoles were prepared for testing as hypoglycemic agents. A number of these containing para-substituted 1-carbonylphenylurea and para-substituted 1-carbamoylbenzenesulfonylurea derivatives were found to possess potent hypoglycemic activity. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00365a023
更新日期：1983-11-01 00:00:00
abstract：:A series of bis(hydroxymethyl)-substituted heterocycles were synthesized and converted to the corresponding bis(methylcarbamate) derivatives. The heterocyclic systems studied were based on 2-phenyl-3-methylfuran (2-4), 1-phenylpyrazole (5-7), 1-phenyl-5-methylpyrazole (9-11), 1-phenyl-5-methylthiophene (13), 1-phenyl-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00378a006
更新日期：1984-12-01 00:00:00
abstract：:The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00058a010
更新日期：1993-03-19 00:00:00
abstract：:A series of 1,2,4-oxadiazoles has been prepared as ester bioisosteres and tested against 15 human rhinovirus serotypes, and the MIC80, the concentration which inhibits 80% or 12 of the serotypes tested, was determined. Homologation of the alkyl group attached to the oxadiazole ring resulted in a reduction in activity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00041a022
更新日期：1994-07-22 00:00:00
abstract：:Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4019178
更新日期：2014-02-27 00:00:00
abstract：:New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were am...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9508503
更新日期：1996-05-24 00:00:00
abstract：:Prealbumin is a major thyroxine binding protein in blood that has been well studied crystallographically and has also been proposed as a model for the thyroxine nuclear receptor in tissue. The high-affinity T4 binding site in prealbumin gave a linear plot on Scatchard analysis. The interactions of selected polychlorin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00155a010
更新日期：1986-05-01 00:00:00
abstract：:Network theory provides one of the most potent analysis tools for the study of complex systems. In this paper, we illustrate the network-based perspective in drug research and how it is coherent with the new paradigm of drug discovery. We first present data sources from which networks are built, then show some example...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01989
更新日期：2020-08-27 00:00:00
abstract：:A common pharmacophore for compounds structurally related to nitraquazone has been derived. Using this pharmacophore, new structures have been designed, synthesized, and evaluated for their inhibitory potencies against cyclic adenosine 5'-monophosphate (cAMP) specific phosphodiesterase (PDE 4). From these compounds, 4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm981012m
更新日期：1998-10-08 00:00:00
abstract：:1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were int...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00225a017
更新日期：1976-03-01 00:00:00
abstract：:A number of new 4(1H)-quinazolinones were synthesized and evaluated in the carrageenin-induced paw edema test. Most of the compounds were obtained by the cyclization of the appropriately substituted anthranilamides with acid chlorides, followed by further chemical transformation. Structure-activity data suggest that 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm50001a006
更新日期：1985-05-01 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：:Two new analogues derived from the platelet activating factor (PAF), containing glucosamine instead of the acetyl group, were synthesized, and their effect on the human keratinocyte cell line HaCaT was evaluated with respect to cytotoxicity, proliferation, adhesion, and migration. Starting with (R)-1,2-isopropylideneg...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050558n
更新日期：2005-10-20 00:00:00
abstract：:Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00230a012
更新日期：1976-08-01 00:00:00
abstract：:TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homologue 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-meth...
journal_title：Journal of medicinal chemistry
pub_type： 评论,杂志文章
doi：10.1021/acs.jmedchem.9b01612
更新日期：2019-10-24 00:00:00
abstract：:In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00386
更新日期：2015-10-08 00:00:00
abstract：:The 2S,3S and 2R,3S diastereoisomers of the hydroxy amino acid 3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA) were synthesized and substituted for the leucyl residues of Leu-Leu-Val-Phe-OCH3 to yield the following analogues: AHMHA-Leu-Val-Phe-OCH3, AHMHA-Val-Phe-OCH3, and Leu-AHMHA-Val-Phe-OCH3. These analogues were ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00347a024
更新日期：1982-05-01 00:00:00
abstract：:For establishment of the structure-activity relationship, 19 heterobicycle-coumarin conjugated compounds with the -SCH(2)- linker were synthesized and found to possess significant antiviral activities. Prominent examples included imidazopyridine-coumarin 12c, purine-coumarin 12d, and benzoxazole-coumarin 14c, which in...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801240d
更新日期：2009-03-12 00:00:00
abstract：:The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01561
更新日期：2019-01-24 00:00:00
abstract：:Kadsurenone, a specific receptor antagonist of platelet-activating factor (PAF), and its analogues were prepared from derivatives of cinnamyl alcohol and (allyloxy)phenol. Racemic kadsurenone, resolvable by a Chiralpak column at low temperatures, has an IC50 value of 2 X 10(-7) M, which is about 50% of the activity of...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00384a023
更新日期：1987-01-01 00:00:00
abstract：:Emericedins A, B, and C, new betaines having inhibitory activity of long chain fatty acid oxidation, were isolated from the culture broth of Emericella quadrilineata IFO 5859. Their structures were determined by spectroscopic analyses as (R)-3-(acylamino)-4-(trimethylammonio)butyrate (acyl: A, acetyl; B, propionyl; C,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00391a030
更新日期：1987-08-01 00:00:00
abstract：:Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010873j
更新日期：2001-09-13 00:00:00
abstract：:The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01357
更新日期：2017-04-13 00:00:00
abstract：:On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049454n
更新日期：2005-03-24 00:00:00
abstract：:Photodynamic therapy uses a combination of light, oxygen, and a photosensitizer to induce the death of malignant cells. To improve the selectivity of a photosensitizer toward cancerous cells that express gonadotropin-releasing hormone (GnRH) receptors, protoporphyrin IX (PpIX) was conjugated to a GnRH agonist, [d-Lys6...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020535y
更新日期：2003-09-11 00:00:00
abstract：:Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8016046
更新日期：2009-08-13 00:00:00
abstract：:The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16-mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. For this purpose, we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300253q
更新日期：2012-07-12 00:00:00
abstract：:A series of trans-platinum(IV) complexes with functionalized aromatic carboxylate ligands, cis,cis,trans-Pt(NH3)2Cl2(CO2C6H4R)2 (R = H (3), p-vinyl (4), p-methoxy (5), p-iodo (6), p-cyano (7), or o-carboxyl (8)) was synthesized and characterized by spectroscopic methods. Crystal structures of 3, 4, 7, and 8 were obtai...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0506468
更新日期：2005-12-15 00:00:00
abstract：:Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400121t
更新日期：2014-03-13 00:00:00
abstract：:A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960170f
更新日期：1996-06-07 00:00:00
