Abstract：
:A series of coumarins and the corresponding 2-thioxocoumarines were prepared and tested for their inhibition profiles against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, II, IX, and XII. The X-ray crystal structure of 6-hydroxy-2-thioxocoumarin bound to hCA II revealed an unprecedented and unexpected inhibition mechanism for this new class of inhibitors when compared to isostructural coumarins. Unlike coumarins which are hydrolyzed by the esterase CA activity to the corresponding 2-hydroxy-cinnamic acid derivatives, the 2-thioxocoumarin was observed intact when bound to hCA II, with its exo-sulfur atom anchored to the zinc-coordinated water molecule, whereas the scaffold establishing favorable contacts with amino acid residues from the active site. This inhibition mechanism is very different from the one observed for hydrolyzed coumarins, which occlude the entrance of the active site cavity. This versatility in the binding mode of coumarins/thioxocoumarins has important consequences for the design of isoform-selective CA inhibitors, some of which are in clinical use or clinical development for various pathologies, among which glaucoma, edema, epilepsy, neuropathic pain, and hypoxic tumors.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Ferraroni M,Carta F,Scozzafava A,Supuran CTdoi
10.1021/acs.jmedchem.5b01720subject
Has Abstractpub_date
2016-01-14 00:00:00pages
462-73issue
1eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章abstract：:Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00403a005
更新日期：1988-08-01 00:00:00
abstract：:Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identif...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101499u
更新日期：2011-04-14 00:00:00
abstract：:As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00157a014
更新日期：1986-07-01 00:00:00
abstract：:A series of α-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101597x
更新日期：2011-04-28 00:00:00
abstract：:Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a019
更新日期：1980-01-01 00:00:00
abstract：:Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01682
更新日期：2019-02-28 00:00:00
abstract：:A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300684u
更新日期：2012-07-26 00:00:00
abstract：:Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characteriz...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200241s
更新日期：2011-07-14 00:00:00
abstract：:The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]- 3,3-dialkyl-1-[[(1-phenylalkyl)-amino]carbonyl]azetidin-2-on es 3 is described in which the C-3 alkyl groups were varied from methyl to butyl as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compounds are discussed ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00013a021
更新日期：1995-06-23 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：:Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801069w
更新日期：2008-12-25 00:00:00
abstract：:(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300396n
更新日期：2012-05-24 00:00:00
abstract：:The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substan...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960281e
更新日期：1996-06-21 00:00:00
abstract：:New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are ca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400529f
更新日期：2013-06-13 00:00:00
abstract：:Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061299k
更新日期：2007-03-08 00:00:00
abstract：:Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC delta C1b domain, we have discovered conveni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900229p
更新日期：2009-07-09 00:00:00
abstract：:Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00114a005
更新日期：1991-10-01 00:00:00
abstract：:Alpha-glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of alpha-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and alpha-glucosidase inhibitory activity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800621x
更新日期：2008-10-09 00:00:00
abstract：:The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3012239
更新日期：2012-11-26 00:00:00
abstract：:The preparation of 6-chloro-5-(cyclopentylmethyl)indan-1-carboxylic acid is described. This acid has good anti-inflammatory and analgesic activities without producing irritation in the gastrointestinal tract up to the highest tested dose. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00369a033
更新日期：1984-03-01 00:00:00
abstract：:The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200464w
更新日期：2011-07-14 00:00:00
abstract：:All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00127a024
更新日期：1989-07-01 00:00:00
abstract：:Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD-ECGF) is an enzyme involved in thymidine metabolism and homeostasis, and its catalytic activity appears to play an important role in angiogenesis. Here we describe the cloning and expression of a His-tagged human TP/PD-ECGF and its assay wi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000037u
更新日期：2000-06-29 00:00:00
abstract：:Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201615t
更新日期：2012-02-09 00:00:00
abstract：:Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00269
更新日期：2019-06-13 00:00:00
abstract：:The synthesis and biological evaluation of the two known phenolic metabolites of paclitaxel are described. The C3'-phenolic metabolite 2 of paclitaxel was prepared from 7-(triethylsilyl)-baccatin III (8) and enantioenriched N-benzoyl-2-azetidinone 7. The C2-phenolic metabolite 3 was synthesized from paclitaxel (1a) vi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960142x
更新日期：1996-07-05 00:00:00
abstract：:Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhibitors. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0493111
更新日期：2004-11-18 00:00:00
abstract：:The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01372
更新日期：2017-12-28 00:00:00
abstract：:Sansalvamide A, a cyclic depsipeptide isolated from a marine fungus of the genus Fusarium, is composed of four hydrophobic amino acids (Phe, two Leu, Val) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry. We have recently synthesized the corr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm048952t
更新日期：2005-05-19 00:00:00
abstract：:The antimicrobial and cytotoxic properties of a series of 9,10-dihydrophenanthrenes structurally related to juncusol (1a), a postulated phytoalexin with confirmed cytotoxic properties, are detailed. Two simple 9,10-dihydrophenanthrenes, 2,7-dihydroxy-3,8-dimethyl-9,10-dihydrophenanthrene (2h, desvinyljuncusol) and 2-h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00148a031
更新日期：1985-10-01 00:00:00
