- Synthesis and Biological Evaluation of Benzodioxole Derivatives as Potential Anticancer and Antioxidant agents
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a series of benzodioxole compounds were synthesized and evaluated for their cytotoxic activity against cervical (Hela), colorectal (Caco-2), and liver (Hep3B) cancer cell lines. Compounds 5a, 5b, 6a, 6b, 7a and 7b showed very weak or negligible anticancer activity with IC50 3.94-9.12 mM. On the contrary, carboxamide containing compounds 2a and 2b showed anticancer activity. Both 2a and 2b reduced Hep3B secretions of α-fetoprotein (α-FP) to 1625.8 ng/ml and 2340 ng/ml, respectively, compared to 2519.17 ng/ml in untreated cells. The results also showed that compound 2a has potent anticancer activity against Hep3B cancer cell line. Furthermore, in cell cycle analysis, compound 2a induced arrest in the G2-M phase in value of 8.07% that was very close to the activity of doxorubicin (7.4%). These results indicate that compound 2a has a potent and promising antitumor activity. However, benzodiazepine derivatives (7a and 7b) showed moderate antioxidant activity with IC50 values of 39.85 and 79.95 μM, respectively compared with the potent antioxidant agent Trolox (IC50 = 7.72 μM).
- Abualhasan, Murad,Amer, Johnny,Daraghmeh, Donia,Daraghmeh, Haifa,Draghmeh, Saja,Eid, Ahmad M,Hawash, Mohammed,Jaradat, Nidal,Mousa, Ahmed,Naser Zaid, Abdel,Sawaftah, Hadeel,Shtayeh, Tahrir
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- B(C6F5)3-catalyzed O-H insertion reactions of diazoalkanes with phosphinic acids
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A highly efficient base-, metal-, and oxidant-free catalytic O-H insertion reaction of diazoalkanes and phosphinic acids in the presence of B(C6F5)3has been developed. This powerful methodology provides a green approach towards the synthesis of a broad spectrum of α-phosphoryloxy carbonyl compounds with good to excellent yields (up to 99% yield). The protocol features the advantages of operational simplicity, high atom economy, practicality, easy scalability and environmental friendliness.
- Jiang, Jun,Zhang, Xinzhi,Zhang, Yangyang,Zhao, Jincheng
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supporting information
p. 5772 - 5776
(2021/07/12)
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- B(C6F5)3-Catalyzed site-selective N1-alkylation of benzotriazoles with diazoalkanes
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Alkylation of benzotriazoles is synthetically challenging, often leading to mixtures of N1 and N2 alkylation. Herein, metal-free catalytic site-selective N1-alkylation of benzotriazoles with diazoalkanes is described in the presence of 10 mol% of B(C6F5)3. These reactions provide N1-alkylated benzotriazoles in good to excellent yields and this protocol is successfully adapted to gram-scale syntheses as well as a derivative with antimicrobial activity.
- Guo, Jing,Mandal, Dipendu,Stephan, Douglas W.,Wu, Yile,Zhao, Yunbo
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supporting information
p. 7758 - 7761
(2021/08/13)
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- Synthesis and biological evaluation of benzodioxol derivatives as cyclooxygenase inhibitors
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Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics; they are competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the conversion of arachidonic acid to inflammatory prostaglandins. Objective: In this study, new benzodioxol derivatives with different core cycles and functional groups (i.e., aryl acetate, aryl acetic acid and diazepine) were designed, synthesized, identified and evaluated for their analgesic and anti-inflammatory activity, as a preliminary screening study to identify the most potent and more selective groups. Methods: The synthesized compounds were identified using FTIR, HRMS,1H-NMR and13C-NMR, and evaluated for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cy-clooxygenase (COX) inhibition assay kit. Results and Discussion: Six compounds were synthesized as a preliminary screening study to identify which was the most potent and more selective group towards COX-2 versus COX-1, compared to ketoprofen as non-selective NSAIDs. The compounds have three different groups: aryl acetate, aryl acetic acid and diazepine. The results showed that the most potent compound against the COX-1 enzyme was 4b (which has diazepine and 2-chlorophenyl) with IC50 = 0.363 μM, and the selectivity ratio of 4b was found to be better than ketoprofen. In contrast, compound 4a (which has diazepine and 3-chlorophenyl) was the most selective with a COX-1/COX-2 ratio value of 0.85 in comparison with a ketoprofen ratio value of 0.20. Conclusion: In general, the synthesized library has moderate activity against both enzymes (i.e., COX-1 and COX-2). Moreover, all six compounds have better COX-2 inhibition selectivity compared to the commercial drug ketoprofen.
- Jaradat, Nidal,Hawash, Mohammed,Abualhasan, Murad
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p. 1117 - 1125
(2020/09/15)
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- PYRIMIDINE SULFAMIDE DERIVATIVE AND PREPARATION METHOD AND MEDICAL APPLICATION THEREOF
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Disclosed are a series of pyrimidine sulfamide compounds and applications thereof in preparing a drug for a disease related to an ETA receptor antagonist. In particular, disclosed is a derived compound represented by formula (I) or a tautomer or pharmaceutically acceptable composition thereof.
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Paragraph 0268-0270
(2020/09/22)
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- Iridium-Catalyzed α-Methylation of α-Aryl Esters Using Methanol as the C1 Source
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IrCl(cod)2]/dppe-catalyzed α-methylation of aryl esters using methanol as the C1 source was developed. This methylation process is useful in several fields including organic chemistry, biochemistry, and medicinal chemistry. Readily available methanol as methylation reagent was successfully adapted. The reaction processed high atom economy and efficient. By applying the reaction system, the synthesis method of naproxen was provided.
- Tsukamoto, Yuya,Itoh, Satoshi,Kobayashi, Masaki,Obora, Yasushi
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supporting information
p. 3299 - 3303
(2019/05/10)
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- A sustainable procedure toward alkyl arylacetates: Palladium-catalysed direct carbonylation of benzyl alcohols in organic carbonates
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A sustainable procedure for the synthesis of various alkyl arylacetates from benzyl alcohols has been developed. With palladium as the catalyst and organic carbonates as the green solvent and in situ activator, benzyl alcohols were carbonylated in an efficient manner without any halogen additives.
- Li, Yahui,Wang, Zechao,Wu, Xiao-Feng
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supporting information
p. 969 - 972
(2018/03/13)
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- Water as a Hydride Source in Palladium-Catalyzed Enantioselective Reductive Heck Reactions
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Pd-catalyzed intramolecular asymmetric carbopalladation of N-aryl acrylamides followed by reduction of C(sp3)-Pd intermediate using diboron–water as a hydride source afforded enantioenriched 3,3-disubstituted oxindoles in high yields and enantioselectivities. When heavy water was used as a deuterium donor in combination with bis(catecholato)diboron (Cat2B2), deuterium was incorporated into the products with high synthetic efficiency. The ligand determined both the enantioselectivity of the reaction and the reaction pathways, thereby affording either hydroarylation (reductive Heck) or carboborylation products.
- Kong, Wangqing,Wang, Qian,Zhu, Jieping
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supporting information
p. 3987 - 3991
(2017/03/27)
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- SUBSTITUTED CATHECHOLS AS INHIBITORS OF IL-4 AND IL-5 FOR THE TREATMENT BRONCHIAL ASTHMA
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The present invention relates to compounds of general formula 1 for the treatment of bronchial asthma by inhibition of IL-4 or IL-5 pathway inhibition. The present invention also relates to the use of compound of general formula 1 for the treatment of bronchial by inhibition of IL-4 or IL-5 pathway. The present invention also relates to the method of treating asthma by inhibition of IL-4 or IL-5 pathway by administration of compound or said composition through oral, intranasal, route or by inhalation to a mammal in need thereof. Compound of general formula 1 may be used for reducing perivascular and peribronchial inflammation.
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Paragraph 0244-0426
(2014/05/20)
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- Palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary carbon stereocenter
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A palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary stereocenter at the 3-position has been achieved by the reaction of γ-methylidene-δ-valerolactones with alkyl isocyanates. High enantioselectivity has been realized by employing a newly synthesized chiral phosphoramidite ligand. The Royal Society of Chemistry 2012.
- Shintani, Ryo,Ito, Tomoaki,Nagamoto, Midori,Otomo, Haruka,Hayashi, Tamio
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supporting information
p. 9936 - 9938
(2012/10/29)
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- INHIBITORS OF PHOSPHATIDYLINOSITOL-3-KINASE (PI3) AND INDUCERS OF NITRIC OXIDE (NO)
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The present invention relates to compounds of general formula 1 for the treatment of malignancy by inhibition of PI3-Akt pathway and or induction of NO. The present invention also relates to the use of compound of general formula 1 for the treatment of malignancy by inhibition of PI3-Akt pathway and or induction of NO. The present invention further relates to a method of treating malignancy by inhibition of PI3-Akt pathway and or induction of NO by administration of compound or said composition to a mammal in need thereof.
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Page/Page column 24-25
(2010/08/04)
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- DEUTERATED ZAMIFENACIN DERIVATIVES
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Disclosed herein are substituted piperidine-based muscarinic receptor modulators of Formula (I), process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof. At least one of the R groups is a deuterium atom.
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- Oxidative rearrangements of arylalkanones with 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide, a 'green' analog of Koser's reagent
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Previous methods for the conversion of arylalkanones to alkyl 2-arylesters by oxidative rearrangement utilized reagents which either produced toxic metal salts or halogenated organics as by-products. In this report, 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide (HMBI) is used to effect this useful transformation, where the reduced iodine reagent is water-soluble and readily recycled.
- Justik, Michael W.
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p. 3003 - 3007
(2008/02/06)
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- Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist
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This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8- methylenedioxy-4H-2,3-benzodiazepin-4-one (±)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo unticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca2+] i in a primary culture of rat cerebellar granule cells which express α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (±)-5 at the AMPA and N-methyl-D-aspartic acid (NMDA) receptors was also evaluated.
- Zappalà, Maria,Postorino, Giovanna,Micale, Nicola,Caccamese, Salvatore,Parrinello, Nunziatina,Grazioso, Giovanni,Roda, Gabriella,Menniti, Frank S.,De Sarro, Giovambattista,Grasso, Silvana
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p. 575 - 581
(2007/10/03)
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- Synthesis and antitumor activity of 1,3-benzodioxole derivatives.
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A series of 1,3-benzodioxoles (5-19) was synthesized and evaluated for their in vitro antitumor activity against human tumor cell lines. Some derivatives exhibited tumor growth inhibition activity. In particular, 6-(4-aminobenzoyl)-1,3-benzodioxole-5-acetic acid methyl ester 8, the most active compound of the series, possesses a significant growth inhibitory activity on 52 cell lines at concentrations ranging from 10(-7) to 10(-5) M.
- Micale, Nicola,Zappala, Maria,Grasso, Silvana
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p. 853 - 859
(2007/10/03)
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- Enantioselective syntheses of dopaminergic (R)- and (S)-benzyltetrahydroisoquinolines
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Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a,b as the major diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing (R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a) and (1R,S)-12b diastereomers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a-16a) bind to D1 and D2 dopamine receptors with affinities 5-15 times higher than those of the corresponding (IR)-enantiomers (14b-16b). Moreover, (1S)-14a inhibits [3H]dopamine uptake with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very important for the search for new active drugs at dopamine receptors.
- Cabedo,Andreu,Ramirez de Arellano,Chagraoui,Serrano,Bermejo,Protais,Cortes
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p. 1794 - 1801
(2007/10/03)
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- Development of orally active nonpeptidic inhibitors of human neutrophil elastase
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5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an α-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure -activity relationships (SARs) are discussed.
- Ohmoto,Yamamoto,Okuma,Horiuchi,Imanishi,Odagaki,Kawabata,Sekioka,Hirota,Matsuoka,Nakai,Toda,Cheronis,Spruce,Gyorkos,Wieczorek
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p. 1268 - 1285
(2007/10/03)
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- SUBSTITUTED 2,3-BENZODIAZEPIN-4-ONES AND THE USE THEREOF
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The invention relates to substituted 2,3-benzodiazepin-4-ones which are antagonists or positive modulators of AMPA receptors, and the use thereof for treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, as well as treating or ameliorating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Down's syndrome, treating, preventing or ameliorating the adverse consequences of the overstimulation of the excitatory amino acids, treating or ameliorating anxiety, psychosis, convulsions, chronic pain, glaucoma, CMV retinitis, urinary incontinence, muscular spasm and inducing anesthesia, as well as for treating or ameliorating the adverse consequences of excitatory amino acid deficiency such as schizophrenia, Alzheimer's disease and malnutrition and neural maldevelopment, and as cognition enhancers. The invention also is directed to the process for the preparation of the substituted 2,3-benzodiazepin-4-ones.
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- Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3- benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists
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A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3- benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5- dihydro-4H-2,3-benzodiazepin-4-one (6), which had an IC50 of 2.7 μM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 μM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 > 100 μM) and weak anticonvulsant (ED60 > 10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.
- Wang, Yan,Konkoy, Christopher S.,Ilyin, Victor I.,Vanover, Kimberly E.,Carter, Richard B.,Weber, Eckard,Keana, John F. W.,Woodward, Richard M.,Cai, Sui Xiong
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p. 2621 - 2625
(2007/10/03)
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- Bone deposition by certain prostaglandin agonists
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Methods for the treatment of bone disorders utilizing certain prostaglandin agonists/antagonists.
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- Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist
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Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. Replacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity while providing a compound with oral bioavailability and longer duration of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ET(A) receptors with a K(i) of 0.43 ± 0.03 nM and an IC50 of 1.4 nM (IC50 for ET(B) = 9800 nM). This compound inhibits ET-1- induced stimulation of phosphoinositide turnover with a K(i) of 0.686 nM and a pA2 of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailability. This compound is one of the most selective ET(A) antagonists reported and therefore is suitable for additional pharmacological and clinical investigation of the role of ET(A) receptors in diseases.
- Wu, Chengde,Chan, Ming F.,Stavros, Fiona,Raju,Okun, Ilya,Mong, Seymour,Keller, Karin M.,Brock, Tommy,Kogan, Timothy P.,Dixon, Richard A. F.
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p. 1690 - 1697
(2007/10/03)
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- Cyclic amide derivatives for treating asthma
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Compounds of formula I STR1 wherein Q1, Q2, Q3, and Q4 have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.
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- BENZIMIDAZOLINONES SUBSTITUTED WITH PHENOXYPHENYLACETIC ACID DERIVATIVES
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Phenoxyphenylacetic acids and derivatives of the general structural formula I STR1 have endothelin antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, pulmonary hypertension, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, endotoxic shock, inflammatory diseases including Raynaud's disease and asthma.
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- Six-membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives
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Phenoxyphenylacetic acids and derivatives of general structural formula I have endothelin STR1 antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, congestive heart failure, postischemic renal failure, vasospasm, cerebral and cardiac ischemia, myocardial infarction, inflammatory diseases, Raynaud's disease, and endotoxic shock, and asthma.
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