- A Unified Catalytic Asymmetric (4+1) and (5+1) Annulation Strategy to Access Chiral Spirooxindole-Fused Oxacycles
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A unified catalytic asymmetric (N+1) (N=4, 5) annulation reaction of oxindoles with bifunctional peroxides has been achieved in the presence of a chiral phase-transfer catalyst (PTC). This general strategy utilizes peroxides as unique bielectrophilic four- or five-atom synthons to participate in the C?C and the subsequent umpolung C?O bond-forming reactions with one-carbon unit nucleophiles, thus providing a distinct method to access the valuable chiral spirooxindole-tetrahydrofurans and -tetrahydropyrans with good yields and high enantioselectivities under mild conditions. DFT calculations were performed to rationalize the origin of high enantioselectivity. The gram-scale syntheses and synthetic utility of the resultant products were also demonstrated.
- Gao, Min,Gong, Xiangnan,Hu, Lin,Luo, Yanshu,Xia, Yuanzhi,Xu, Qianlan,Zhao, Yukun
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supporting information
p. 19813 - 19820
(2021/08/03)
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- Synthesis and cytotoxic studies of novel 5-phenylisatin derivatives and their anti-migration and anti-angiogenic evaluation
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A number of 5-arylisatin derivatives were synthesized in 5–6 steps from readily available starting materials. Their structures were confirmed by 1H NMR and 13C NMR as well as LC/MS. The cytotoxicity of these novel isatins against human leukemia K562 cells were evaluated by MTT assay in vitro. SAR studies indicated that the N-substituted benzyl and C-5 substituted phenyl groups greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 present in the parent ring is required to maintain such a potency. Particularly, N-(p-methoxybenzyl)-5-(p-methoxyphenyl)isatin (compound 2m) showed the highest antitumor activity against K562 cell lines (IC50 = 0.03 μM). Moreover, treatment with compound 2m significantly inhibited liver cancer HepG2 cells proliferation and migration, which could also reduce the human umbilical vein endothelial cells (HUVEC) tube formation. In conclusion, compound 2m exhibited very good cancer cells proliferation inhibition by angiogenesis responses in vitro, and 2m might be a promising angiogenesis inhibitor for cancer treatment.
- Zhang, Qian,Teng, Yuou,Yuan, Yuan,Ruan, Tingting,Wang, Qi,Gao, Xing,Zhou, Yao,Han, Kailin,Yu, Peng,Lu, Kui
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p. 800 - 814
(2018/07/29)
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- Oxindole-based intraocular pressure reducing agents
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The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6?h) of the lead-compound. This effect in combination with high IOP reducing effect (41?±?6%) in low concentrations of the active compound (0.1?wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.
- Zaryanova, Ekaterina V.,Lozinskaya, Nataly A.,Beznos, Olga V.,Volkova, Maria S.,Chesnokova, Nataly B.,Zefirov, Nikolay S.
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supporting information
p. 3787 - 3793
(2017/07/27)
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- Synthesis and anti-cancer activity evaluation of 5-(2-carboxyethenyl)-isatin derivatives
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A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro. SAR study suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of it's mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells.
- Teng, Yu-Ou,Zhao, Hong-Ye,Wang, Jing,Liu, Huan,Gao, Mei-Le,Zhou, Yao,Han, Kai-Lin,Sun, Hua,Yu, Peng,Fan, Zhen-Chuan,Zhang, Yong-Min
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p. 145 - 156
(2018/05/02)
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- A cinchona alkaloid catalyzed enantioselective sulfa-Michael/aldol cascade reaction of isoindigos: Construction of chiral bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters
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A cinchona alkaloid catalyzed diastereoselective and enantioselective sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and isoindigos has been successfully developed to afford the highly congested bispirooxindole tetrahydrothiophenes with vicinal quaternary spirocenters in high yields (up to 91%), excellent diastereoselectivities (up to >20 : 1 dr), and good enantioselectivities (up to 98% ee). Some synthetic transformations of the reaction products were also studied.
- Gui, Yong-Yuan,Yang, Jian,Qi, Liang-Wen,Wang, Xiao,Tian, Fang,Li, Xiao-Nian,Peng, Lin,Wang, Li-Xin
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supporting information
p. 6371 - 6379
(2015/06/08)
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- Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans
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A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6′-chloro-5-(4-fluorophenyl)-7′-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3′-1H-indole]-2′,4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy. Synergy from stereochemical complexity: An attempt to synthesize analogues of a known spiroindolinone led to a series of diastereomers. One spiroindolinone, termed synazo-1, was shown to exhibit potent activity (300 pM) against C. albicans in the presence of fluconazole. Synazo-1 is a true synergizer and was also highly active against some drug-resistant C. albicans strains.
- Premachandra, Ilandari Dewage Udara Anulal,Scott, Kevin A.,Shen, Chengtian,Wang, Fuqiang,Lane, Shelley,Liu, Haoping,Van Vranken, David L.
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p. 1672 - 1686
(2015/10/06)
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- Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors
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The Severe Acute Respiratory Syndrome (SARS) is a serious life-threatening and strikingly mortal respiratory illness caused by SARS-CoV. SARS-CoV which contains a chymotrypsin-like main protease analogous to that of the main picornavirus protease, 3CLpro. 3CLpro plays a pivotal role in the viral replication cycle and is a potential target for SARS inhibitor development. A series of isatin derivatives as possible SARS-CoV 3CL pro inhibitors was designed, synthesized, and evaluated by in vitro protease assay using fluorogenic substrate peptide, in which several showed potent inhibition against the 3CLpro. Structure-activity relationship was analyzed, and possible binding interaction modes were proposed by molecular docking studies. Among all compounds, 8k1 showed most potent inhibitory activity against 3CLpro (IC50 = 1.04 μM). These results indicated that these inhibitors could be potentially developed into anti-SARS drugs.
- Liu, Wei,Zhu, He-Min,Niu, Guo-Jun,Shi, En-Zhi,Chen, Jie,Sun, Bo,Chen, Wei-Qiang,Zhou, Hong-Gang,Yang, Cheng
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p. 292 - 302
(2014/01/17)
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- Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl)isatin derivatives as anticancer agents
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Forty four di- or trisubstituted novel isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of these new isatin derivatives against three human tumor cell lines, K562, HepG2 and HT-29, were evaluated by MTT assay in vitro. SAR studies suggested that the combination of 1-benzyl and 5-[trans-2- (methoxycarbonyl)ethen-1-yl] substitution greatly enhance their cytotoxic activity, whereas an intact carbonyl functionality on C-3 as present in the parent ring is required to such a potency. This study leads to the identification of two highly active molecules, compounds 2h (IC50 = 3 nM) and 2k (IC50 = 6 nM), against human leukemia K562 cells.
- Han, Kailin,Zhou, Yao,Liu, Fengxi,Guo, Qiannan,Wang, Pengfei,Yang, Yao,Song, Binbin,Liu, Wei,Yao, Qingwei,Teng, Yuou,Yu, Peng
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supporting information
p. 591 - 594
(2014/01/23)
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- Simple synthesis of some 2-substituted melatonin derivatives
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A simple strategy for the synthesis of some 2-substituted melatonin derivatives using p-anisidine as starting material is reported. The key step is a chemoselective reduction of a cyano group in the presence of an appropriate acid anhydride by hydrogenation over Adams' catalyst or with sodium borohydride in the presence of catalytic amounts of anhydrous nickel(II) chloride. The 2-substituted melatonin derivatives were obtained in six or seven steps from inexpensive p-anisidine in 9-13% overall yield. Georg Thieme Verlag Stuttgart New York.
- Lozinskaya, Natalia A.,Sosonyuk, Sergey E.,Volkova, Maria S.,Seliverstov, Michael Yu.,Proskurnina, Marina V.,Bachurin, Sergey E.,Zefirov, Nikolay S.
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experimental part
p. 273 - 276
(2011/03/18)
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- Synthesis of benzotriazine and aryltriazene derivatives starting from 2-azidobenzonitrile derivatives
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3-Substituted 3,4-dihydro-4-imino-1,2,3-benzotriazine derivatives 7 were formed from 2-azidobenzonitriles 4 as starting materials on treatment with Grignard or lithium organic reagents. In some cases these procedures gave aryltriazenes 10 and 11 as products. All compounds were identified by NMR spectroscopy and the structures of three products, namely 7a, 10a and 11i, were corroborated by X-ray crystallography. The reactions of 2-azidobenzonitrile derivatives with Grignard reagents have been investigated. These reactions, depending on the type of Grignard reagent and the substituents on the 2-azidobenzonitrile derivatives, resulted in benzotriazines and triazenes. Copyright
- Nakhai, Azadeh,Stensland, Birgitta,Svensson, Per H.,Bergman, Jan
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experimental part
p. 6588 - 6599
(2011/02/26)
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- Metal complex dye for a photoelectrochemical cell
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The first metal complex dye comprising a metal atom, bidentate or tridentate ligand(s) having nitrogen atoms, and monodentate or bidentate ligand(s) which coordinates to the metal atom via an acyloxy group, a 1,3-diketo group, etc. has a high stability to heat and light, and can efficiently sensitize semiconductor particles. The first photoelectric conversion device comprising the first dye exhibits a high stability to heat and light, and an excellent photoelectric conversion efficiency. The second metal complex dye comprising a metal atom, bidentate ligand(s) with a particular structure, and optional bidentate or tridentate ligand(s) having nitrogen atoms and a monodentate or bidentate ligand(s) such as 1,3-diketones, etc. has a high absorbancy at a large wave range, and can efficiently sensitize semiconductor particles. The second photoelectric conversion device comprising the second dye exhibits an excellent photoelectric conversion efficiency. These photoelectric conversion devices are useful for a photo-electrochemical cell.
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Page/Page column 37-39
(2008/06/13)
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- Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors
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The present invention is directed to a class indolinone compounds, hexahydro-cyclohepta-pyrrole oxindoles, which are useful as protein kinase inhibitors.
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Page/Page column 20
(2010/02/08)
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to novel pyrrole substituted 2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-heteroarylidene-2-indolinone protein kinase inhibitors
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The present invention relates to novel 3-heteroarylidene-2-indolinone compounds and physiologically acceptable salts thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-(cycloalkanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkano-heteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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Page column 25
(2010/02/05)
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- 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkanoheteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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- Microwave assisted preparation of isatins and synthesis of (±)- convolutamydine-A
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Microwave assisted preparation of a number of isatin derivatives is reported. A simple synthesis of (±)-convolutamydine-A, a potent compound against leukemia cells, is presented.
- Jnaneshwara,Bedekar,Deshpande
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p. 3627 - 3633
(2007/10/03)
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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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