- Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides
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Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.
- Schilling, Waldemar,Zhang, Yu,Riemer, Daniel,Das, Shoubhik
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supporting information
p. 390 - 395
(2019/12/15)
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- Ruthenium-Catalyzed Asymmetric Allylic Alkylation of Isatins
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A new ruthenium-based catalytic system for branched-selective asymmetric allylic alkylation is disclosed and applied to the synthesis of chiral isatin derivatives. The catalyst, which is generated in situ from commercially available CpRu(MeCN)3PF6 and a BINOL-derived phosphoramidite, is both highly active (TON up to 180) and insensitive to air and moisture. Additionally, the N-alkylated isatins accessible using this methodology are versatile building blocks that are readily transformed into chiral analogs of achiral drug molecules.
- Kalnmals, Christopher A.,Parkin, Sean,Ramakrishnan, Divya,Ryan, Michael C.,Smaha, Rebecca W.,Trost, Barry M.
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supporting information
(2020/04/02)
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- Synthesis of substituted tryptanthrin via aryl halides and amines as antitumor and anti-MRSA agents
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The natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), and its analogues are found to exhibit potent antitumor and anti-MRSA activities. An efficient and convenient method has been developed for the synthesis of tryptanthrin D-ring derivatives through the reaction of substituted tryptanthrins and secondary amines in moderate to good yields. Some of the new compounds exhibited antitumor activities against the human tumor cell lines A549, HCT116 and MDA-MB-231, with mean IC50 values at low micromolar levels. In addition, some of the compounds showed excellent anti-MRSA activities and were more effective than vancomycin, with MIC values of 0.31–1.25 μg/mL for Mu50,RN4220, and Newman strains.
- Chen, Huan,Hou, Baolong,Liu, Jianli,Liu, Li,Ma, Xiumei,Wang, Cuiling,Wang, Jilin,Wang, Rui,Wang, Yinyin,Zheng, Xudong
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- Utilizing Solubility differences to achieve regiocontrol in the synthesis of substituted quinoline-4-carboxylic acids
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A practical method for the regiocontrolled synthesis of substituted quinoline-4-carboxylic acids is described. Solubility differences between the product quinoline regioisomers enable their facile separation, thus avoiding any challenging chromatographic purifications and allowing access to highly substituted quinoline compounds in three steps from commercially available anilines.
- Lindsay-Scott, Peter J.,Barlow, Helen
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supporting information
p. 1516 - 1520
(2016/06/14)
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- Synthesis and antifungal activity of 1-aminomethyl-3-{4- (chlorobenzyloxy) benzoylhydrazono}-4, 5/5, 6-dichloroindolin-2- ones
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3-{4-(Chlorobenzyloxy) benzoylhydrazono}-4,5/5,6-dichloroindolin-2-ones 1a,b-5a,b, were synthesized by the condensation of 4-(chlorobenzyloxy) benzoylhydrazines and 4, 5/5, 6-dichloroindolin-2,3-diones. Compounds 1a,b-5a,b when subjected to Mannich reaction with secondary heterocyclic amines in the presence of formaldehyde, furnished 1-aminomethyl-3-{4-(chlorobenzyloxy) benzoylhydrazono}-4, 5/5, 6-dichloroindolin-2- ones 6a,b-20a,b. The structures of the compounds have been established by means of spectral (IR and 1H NMR) and elemental analysis. The compounds have been screened for their antifungal potential against human pathogenic fungi.
- Harrison, Darwin Anil,Rastogi, Nisheeth,Rahman, Masihur
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p. 411 - 418
(2019/01/21)
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- Synthesis and structure-activity relationship studies of small molecule disruptors of EWS-FLI1 interactions in Ewing's sarcoma
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EWS-FLI1 is an oncogenic fusion protein implicated in the development of Ewing's sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition of the analogues was measured by an EWS-FLI1/NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cells containing EWS-FLI1 (TC32 and TC71) and control PANC1 cell lines devoid of the oncoprotein. Our data revealed that substitution of electron donating groups at the para-position on the phenyl ring was the most favorable for inhibition of EWS-FLI1 by analogs of 2. Compound 9u (with a dimethylamino substitution) was the most active inhibitor with GI50 = 0.26 ± 0.1 μM. Further, a correlation of growth inhibition (EWS-FLI1 expressing TC32 cells) and the luciferase reporter activity was established (R2 = 0.84). Finally, we designed and synthesized a biotinylated analogue and determined the binding affinity for recombinant EWS-FLI1 (Kd = 4.8 ± 2.6 μM).
- Tosso, Perrer N.,Kong, Yali,Scher, Lauren,Cummins, Ryan,Schneider, Jeffrey,Rahim, Said,Holman, K. Travis,Toretsky, Jeffrey,Wang, Kan,üren, Aykut,Brown, Milton L.
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p. 10290 - 10303
(2015/02/19)
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- INDIRUBIN-TYPE COMPOUNDS, COMPOSITIONS, AND METHODS FOR THEIR USE
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Compounds and compositions including 6-bromo-indirubin, 5-amino-indirubin and N-methyl-indirubins and related indirubin derivatives are provided that are useful as selective modulators of glycogen synthase kinase-3, cyclin-dependent protein kinases or aryl hydrocarbon receptors. Methods of inhibiting or modulating cell growth or cell cycling are provided using the compounds of the invention. In other aspects, compounds and methods for the treatment of protozoan-mediated diseases, Alzheimer's disease and diabetes are provided.
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Page/Page column 24; Figure 2A
(2008/06/13)
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- 1-Substituted pyrazolo[1,5-c]quinazolines as novel Gly/NMDA receptor antagonists: Synthesis, biological evaluation, and molecular modeling study
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A new set of 5,6-dihydro-pyrazolo[1,5-c]quinazoline-2-carboxylates (2-18), bearing different substituents (COOEt, Cl, Br, CH3, and COOH) at position-1, were synthesized in order to investigate the influence of various groups at this specific position on Gly/NMDA receptor affinity and/or selectivity. All the herein reported compounds were evaluated for their binding at the Gly/NMDA, AMPA, and KA receptors. Some selected compounds were also tested for their functional antagonistic activity at both the AMPA and NMDA receptor-ion channels. The results obtained in this study have highlighted that a C-1 lipophilic substituent on the pyrazolo[1,5-c]quinazoline-2-carboxylate core shifts selectivity toward the Gly/NMDA receptor, while a C-1 anionic carboxylate residue is able to increase affinity toward this receptor subtype. In particular, the 2-carboxylic acids 15 and 16, bearing a chlorine atom at position-1, are not only potent (Ki = 0.18 and 0.16 μM, respectively), but also highly Gly/NMDA versus AMPA selective (selectivity ratio > 500). Furthermore, the 1,2-dicarboxylic acids 13 and 14 are endowed with the highest Gly/NMDA receptor binding activity (Ki = 0.09 and 0.059 μM, respectively), among the pyrazoloquinazoline series of derivatives. A molecular modeling study has been carried out to better understand receptor affinity and selectivity of these new pyrazoloquinazoline derivatives.
- Varano, Flavia,Catarzi, Daniela,Colotta, Vittoria,Calabri, Francesca Romana,Lenzi, Ombretta,Filacchioni, Guido,Galli, Alessandro,Costagli, Chiara,Deflorian, Francesca,Moro, Stefano
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p. 5536 - 5549
(2007/10/03)
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- Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases
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Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3β, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.
- Polychronopoulos, Panagiotis,Magiatis, Prokopios,Skaltsounis, Alexios-Leandros,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Tarricone, Aldo,Musacchio, Andrea,Roe, S. Mark,Pearl, Laurence,Leost, Maryse,Greengard, Paul,Meijer, Laurent
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p. 935 - 946
(2007/10/03)
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- Phenylsulfonyl-1,3-dihydro-2h-indole-2-one derivatives, their preparation and their therapeutic use
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The invention relates to compounds of formula: and also to the salts thereof with mineral or organic acids, and the solvates and/or hydrates thereof, with affinity for and selectivity towards the arginine-vasopressin V1b receptors and/or for the ocytocin receptors and, furthermore, for certain compounds, affinity for the V1a receptors. The invention also relates to the process for preparing them, to the intermediate compounds of formula (IV) that are useful for preparing them, to pharmaceutical compositions containing them and to their use for preparing medicinal products.
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Page/Page column 20
(2010/02/08)
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- An improved procedure for the regiospecific synthesis of electron deficient 4- and 6-substituted isatins
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The regiospecific synthesis of 4- and 6-substituted isatins 5a-g in four steps from halonitrobenzenes 1a-g has been investigated for a variety of substrates (Scheme 1). The procedure makes use of readily available, easily handled materials and in most cases purification of neither intermediates nor final products is required. Yields of isatins are between 26 and 75% (Table 1). Improved yields of known isatins are reported as well as the syntheses of previously unreported isatins. This method, taken together with known procedures, provides for the synthesis of the full complement of isatin regioisomers.
- Kraynack, Erica A.,Dalgard, Jackline E.,Gaeta, Federico C. A.
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p. 7679 - 7682
(2007/10/03)
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- Glycine receptor antagonist pharmacophore
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Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer''s disease, amyotrophic lateral sclerosis, Huntington''s disease and Down''s syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions and inducing anesthesia are disclosed by administering to an animal in need of such treatment a compound which has high binding to the glycine receptor.
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- Biological activities and quantitative structure-activity relationships of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones as aldose reductase inhibitors
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A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'- halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'- chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline]-2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure- activity relationships in this series are also discussed.
- Yamagishi,Yamada,Ozaki,Asao,Shimizu,Suzuki,Matsumoto,Matsuoka,Matsumoto
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p. 2085 - 2094
(2007/10/02)
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