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At least 595 records · Page 33Linked to original sources
PubMed1992

Synthesis of the acridone alkaloids glyfoline and congeners. Structure-activity relationship studies of cytotoxic acridones.

Glyfoline (4, 1,6-dihydroxy-10-methyl-2,3,4,5-tetramethoxyacridin-9-one) and its congeners were synthesized for evaluation of their cytotoxicity. A detailed structure-activity relationships (SAR) of these acridone derivatives were also studied. To study the SAR of glyfoline analogues, substituent(s) at C-1 and C-6 and at the heterocyclic nitrogen of glyfoline nucleus were modified. Nitro- and amino-substituted glyfoline analogues were also synthesized to study the effects of substituent(s) (electron-withdrawing vs electron-donating) on their cytotoxicity. These compounds were synthesized via the Ullmann condensation of anthranilic acids with iodobenzenes or 2-chlorobenzoic acids with aniline derivatives. The SAR studies showed that 1-hydroxy-9-acridones were more active than their 1-OMe derivatives against cell growth of human leukemic HL-60 cells in culture. Replacement of NMe of glyfoline with NH or N(CH2)2NEt2 resulted in either total loss or dramatic reduction of cytotoxicity. Glyfoline congeners with nitro function at the A-ring were inactive, while compounds with amino substituent were shown to be cytotoxic in vitro.

Acridines↗
PubMed1984

Synthesis of previously inaccessible quinazolines and 1,4-benzodiazepines as potential anticonvulsants.

A series of 4,6,7,8- tetrasubstituted 3,4- dihydroquinazolines , quinazolines, quinazolin -2-ones, 1,2,3,4- tetrahydroquinazolin -2-ones, and 5,7,8,9- tetrasubstituted 1,4-benzodiazepines have been synthesized by utilizing the Diels -Alder reaction between furan o-amino nitriles and various alkyl or aryl vinyl ketone dienophiles to obtain the anthranilic acid precursors. All of the newly synthesized target compounds were evaluated in mice for anticonvulsant activity. Pro- and anticonvulsant action was quantified by the timed intravenous pentylenetetrazol seizure threshold method. Selected compounds were also evaluated for benzodiazepine receptor binding properties and in vivo antagonist potential. Although the compounds lack potency, the data suggest that previously inaccessible substituted analogues may be useful to segregate the proconvulsant , anticonvulsant, and antagonist actions of benzodiazepines and quinazolines.

Animals↗
PubMed1997

Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain.

The observation that anthranilic acid as N-terminal group produces a dramatic increase of the binding affinity of the phosphopeptide sequence Glu-pTyr-Ile-Asn for the Grb2-SH2 domain was rationalized by molecular modeling. The model, which invokes a stacking interaction between the N-terminal group and the SH2 domain residue Arg alpha A2, was subsequently used to design the 3-aminobenzyloxycarbonyl N-terminal group. The latter confers high affinity (IC50 = 65 nM in an ELISA assay) to the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Facile preparation of benzo[4,5]thieno[2,3-b]pyridines and naphtho[b-4,5]thieno[2,3-b]pyridines via the reaction of Barton esters and benzynes.

Titled compounds were prepared in a one-pot synthesis by generating symmetrically substituted benzyne intermediates by the diazotization of anthranilic acids in the presence of Barton esters. Unsymmetrically substituted aryne either gave mixtures of regioisomers or failed. However, nitro and methyl derivatives of titled compounds could be obtained as single products using appropriately substituted Barton esters.

Journal Article↗
PubMed2003

Total synthesis of (-)-fumiquinazolines A, B, C, E, H, and I. Approaches to the synthesis of fiscalin A.

The first syntheses of (-)-fumiquinazolines A, B, and I, which proceed in 14 steps from protected tryptophan, anthranilic acid, leucine, and alanine in 7% overall yield, are described. Tricycle 30 was formed by a palladium-catalyzed cyclization. Oxidation of 30a with saccharine-derived oxaziridine 21 for fumiquinazolines A and B and oxidation of 30b with dimethyldioxirane for fumiquinazoline I selectively formed the appropriate imidazoindolone stereoisomers. Application of the Ganesan-Mazurkiewicz cyclization completed the syntheses. Efficient 14-step syntheses of (-)-fumiquinazolines C (7) and E (3) and a 15-step synthesis of (-)-fumiquinazoline H (8) using FmocNHCH(CH2SePh)CO2H as a dehydroalanine precursor that spontaneously eliminated benzeneselenol without oxidation under the cyclization conditions are also reported. Model 86 for fiscalins A with the H and OH anti to each other has been prepared, but the procedure that worked for the model failed with the fully functionalized side chain.

Catalysis↗
PubMed2004

Preparation and resolution of a modular class of axially chiral quinazoline-containing ligands and their application in asymmetric rhodium-catalyzed olefin hydroboration.

The preparation and resolution of a series of axially chiral quinazoline-containing ligands is described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation, the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles derived from the racemic phosphinamines and (+)-di-mu-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C2,N]dipalladium(II) were separated by fractional crystallization. The configuration of the resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving excellent conversions, good to complete regioselectivities, and the highest enantioselectivities obtained to date for several members of the vinylarene class, including cis-beta-methylstyrene (97%), cis-stilbene (99%), and indene (99.5%).

Journal Article↗
PubMed2003

Lilacinone, a red aminobenzoquinone pigment from Lactarius lilacinus.

A red pigment, lilacinone (1), was isolated from fruit bodies of the toadstool Lactarius lilacinus. Its structure was established by 2D NMR and APCIMS methods. Compound 1 is a novel type of fungal aminobenzoquinone pigment and may be biosynthetically derived from three molecules of anthranilic acid.

Agaricales↗
PubMed1995

Structure-activity relationships of norditerpenoid alkaloids occurring in toxic larkspur (Delphinium) species.

Fourteen norditerpenoid alkaloids present in larkspur (Delphinium) species associated with cattle poisoning on grazing land in the western United States have been toxicologically assessed in a mouse bioassay. Toxicity data for these alkaloids have established the tertiary nitrogen atom and anthranilic acid esterification as important structural features necessary to impart toxicity to lycoctonine-type norditerpenoid alkaloids. Variation in C-14 functionality of the toxic alkaloids is also a factor that influences toxicity in these compounds. The relationship of the structure-activity information of this study to previous in vitro neuromuscular studies is discussed.

Alkaloids↗
PubMed2001

8,9-Didehydrofluoranthenes as building blocks for the synthesis of extended polycyclic aromatic hydrocarbons (PAHs).

[reaction: see text] The synthesis of phenyl-substituted 8,9-dibromofluoranthene and p-dodecylphenyl-substituted 8,9-fluoranthene anthranilic acid is presented. Their synthetic potential as 8,9-didehydrofluoranthene precursors is demonstrated in combination with a new biscyclopentadienone by the synthesis of novel phenyl-substituted PAHs with up to 14 annulated rings. The crystal structure of 7,16-diphenylfluorantheno[8,9-k]fluoranthene is given.

Journal Article↗
PubMed2003

A concise total synthesis of (+/-)-alantrypinone by a novel hetero-Diels-Alder reaction.

[reaction: see text] An efficient total synthesis of (+/-)-alantrypinone (1) and its 17-epi isomer (17) has been accomplished employing a novel aza-Diels-Alder reaction as the key step. The reaction sequence comprises 8 steps starting from anthranilic acid and proceeds in 13.5% overall yield. An interesting anionic equilibration between 1 and its epimer 17 has also been discovered.

Journal Article↗
PubMed2006

New aminophenoxazinones from a marine Halomonas sp.: fermentation, structure elucidation, and biological activity.

The addition of anthranilic acid to the culture medium of the marine derived Halomonas sp. strain GWS-BW-H8hM completely altered the secondary metabolite pattern relative to the standard conditions. The red-orange color of the culture filtrate extract was the result of the production of 2-aminophenoxazin-3-one (1), chandrananimycin C (5) and three new derivatives of 1 with a previously unknown substitution pattern: 2-amino-, 2-amino-8-benzoyl-, and 2-amino-8-(4-hydroxybenzoyl)-6-hydroxyphenoxazin-3-one (2-4). The compounds were determined to have antibacterial and cytotoxic activities; a mode of action other than DNA intercalation is discussed.

Anti-Bacterial Agents↗
PubMed1999

The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein.

1 The kinetics and nature of equilibrium binding were used to characterize the molecular interaction of the anthranilic acid derivative [3H]-XR9576 with the multidrug resistance P-glycoprotein (P-gp). XR9576 displayed specific high-affinity binding to P-gp (Bmax = 275 pmol mg-1, Kd = 5.1 nM). The transport substrates [3H]-vinblastine and [3H]-paclitaxel displayed 4 fold and 20 fold lower affinity respectively for P-gp. The duration of action of XR9576 with P-gp was increased in comparison to that of vinblastine which displayed a slower rate of association and a faster dissociation rate. 2 The relative affinities of several modulators and transport substrates to interact with P-gp were determined from displacement drug equilibrium binding assays. Vinblastine and paclitaxel could only fractionally displace [3H]-XR9576 binding, displaying Ki values significantly different from their measured Kd values. This suggests a non-competitive interaction between XR9576 and the P-gp substrates vinblastine and paclitaxel. 3 XR9576 was shown to be a potent modulator of P-gp mediated [3H]-vinblastine and [3H]-paclitaxel transport as it increased the steady-state accumulation of these cytotoxics in CHrB30 cells to levels observed in non-P-gp-expressing AuxB1 cells (EC50 = 487+/-50 nM). This inhibition of drug transport is not mediated through competition for transport since [3H]-XR9576 accumulation was not influenced by P-gp expression or function. 4 These results demonstrate that the P-gp modulator XR9576 exhibits greater selectivity, duration of inhibition and potency of interaction with this transporter than any other reported modulators. Several lines of evidence suggest that XR9576 inhibits P-gp function by binding at a site which is distinct from the site of interaction of transport substrates. The two sites may be classified as serving modulatory or transport functions.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Tranilast attenuates connective tissue growth factor-induced extracellular matrix accumulation in renal cells.

Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid) is a synthetic compound that we have recently reported to inhibit transforming growth factor-beta1 (TGF-beta1)-induced tubulointerstitial fibrosis in the kidney. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of TGF-beta1. Both proximal tubule cells (PTCs) and cortical fibroblasts (CFs) are considered to be responsible for the production of tubulointerstitial extracellular matrix (ECM). These studies were undertaken to assess the profibrotic effects of CTGF in an in vitro model of the human PTCs and CFs, and to determine whether tranilast is effective in limiting the in vitro matrix responses induced by CTGF. Primary cultures of PTCs and CFs were exposed to CTGF (20 ng/ml)+/-tranilast (100 microM). Cell hypertrophy and the secretion of the ECM proteins fibronectin and collagen IV were determined. The effects of tranilast on TGF-beta1-induced CTGF mRNA expression and on phosphorylation of Smad2 were determined. CTGF significantly induced cell hypertrophy, increased fibronectin, and collagen IV secretion in PTCs and CFs. In all cases, the CTGF-induced increase in ECM protein was inhibited in the presence of tranilast. Tranilast reduced CTGF mRNA and phosphorylation of Smad2, which were induced by TGF-beta1 in PTCs and CFs. These results suggest that tranilast is a potential effective antifibrotic compound in the kidney, exerting its effects via inhibition of TGF-beta1-induced CTGF expression and downstream activation of the Smad2 pathway in both PTCs and CFs.

Anti-Allergic Agents↗
PubMed2004

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia.

Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)(7)/(TA)(7) genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 x 10(-22)). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.

Dinucleotide Repeats↗
PubMed2005

Practical synthesis of potential endothelin receptor antagonists of 1,4-benzodiazepine-2,5-dione derivatives bearing substituents at the C3-, N1- and N4-positions.

The expedient synthesis of various 1,4-benzodiazepine-2,5-dione compounds, particularly those having substituents at the C3-, N1- and N4-positions is achieved. The important features in these synthetic strategies include: (i) using the coupling reaction of isatoic anhydride with alpha-amino ester for direct construction of the core structure of 1,4-benzodiazepine-2,5-dione; (ii) using potassium carbonate as the base of choice for selective alkylation at the N1-site, while using lithiated 2-ethylacetanilide as the required base to furnish the N4-alkylation; and (iii) using 2-nitrobenzoyl chloride as a synthetic equivalent of anthranilic acid to facilitate the polyethylene resin-bound liquid-phase combinatorial synthesis. The prepared 1,4-benzodiazepine-2,5-dione compounds are evaluated for endothelin receptor antagonism by a functional assay that measures the inhibitory activity against the change of intramolecular calcium ion concentration induced by endothelin-1. The preliminary results indicate that 1,4-benzodiazepine-2,5-diones bearing two flanked aryl substituents at the N1- and N4-sites show better inhibitory activity than the corresponding unalkylated and N-monoalkylated compounds. A promising candidate, 1-benzyl-7-chloro-3-isopropyl-4-(3-methoxybenzyl)-1,4-benzodiazepine-2,5-dione (17b), exhibits an IC50 value in low nM range.

Animals↗