- Synthesis of phidianidines A and B
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Reaction of a substituted indole-3-acetyl chloride with N-5-azidopentyl-N′-hydroxyguanidine generated a substituted 3-(5-azidopentylamino)-5-((indol-3-yl)methyl)-1,2,4-oxadiazole. Reduction of the azide with zinc and ammonium formate afforded the amine, which was elaborated to the guanidine, completing short and efficient syntheses of the cytotoxic natural products phidianidines A and B in 19% overall yield by a convergent route that will make analogues readily available for biological evaluation. Initial screening in the NCI 60 cell line at 10-5 M indicated that the bromine on the indole is necessary for activity and that the amine precursor to phidianidine A is more potent than phidianidine A.
- Lin, Hong-Yu,Snider, Barry B.
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- First practical and efficient synthesis of 3-phosphorylated β-carboline derivatives using the Pictet-Spengler reaction
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We report here the first practical and efficient synthesis of the diethyl 1,2,3,4-tetrahydro-β-carboline-3-phosphonates 3 and 4 as well as diethyl 9H-β-carboline-3-phosphonates 5 and 6. The target compounds were prepared in good yields by application of t
- Viveros-Ceballos, Jos Luis,Sayago, Francisco J.,Cativiela, Carlos,Ordez, Mario
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- Concise total synthesis of phidianidine A and B
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The shortest total synthesis of cytotoxic indole alkaloids phidianidine A and B is described. Rapid assembly of the 1,2,4-oxadiazole core from a novel N-hydroxyguanidine and the corresponding indole-3-acetic acid chloride led to formal syntheses of phidianidine A and B in only three steps from known compounds. Deprotection under standard conditions provided the trifluoroacetate salts of phidianidine A and B in quantitative yield.
- Buchanan, Jacob C.,Petersen, Brandon P.,Chamberland, Stephen
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- Synthesis of Novel N,N-Disubstituted Ethyl P-[2-(1 H-Indol-3-YL)Acetyl]Phosphoramidates and Their Biological Activity
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A series of novel N,N-disubstituted ethyl P-[2-(1H-indol-3-yl)acetyl]phosphoramid-ates were synthesized. All title compounds were characterized by IR, NMR (1H, 13C, 31P) spectra, mass spectra, and C, H, N analysis. The anticancer activity of the title compounds was evaluated in two human cell lines MCF-7 (breast cancer) and HeLa (Cervical cancer) cell lines by the use of the MTT assay, and the IC50 values were determined. The derivatives with substituted piperazines exhibited significant cytotoxicity against the tested cell lines at 5 μM and displayed low IC50 values in the region of 5.8-8.8 μM for MCF-7 cell lines and 14.8-16.4 μM for HeLa cell lines when compared with the standard doxorubicin (5.4 and 14.2 μM).
- Venkata Ramana,Madhava,Ravendra Babu,Subbarao,Hema Kumar,Naga Raju
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- Observations arising from a Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A
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An overview of an iterative Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A is described. In a preliminary model study, the (E)-oxime 10 underwent Beckmann rearrangement to give the bisindolylacetamide 4 followed by an intramolecular Mannich cyclization affording 2-(indolin-2-yl)indole 5 containing the heterocyclic framework of the iheyamine alkaloids. However, the 2-(indolin-2-yl)indole 5 could not be converted into the azepinobisindole core of iheyamine A. When the same Beckmann-Mannich approach was applied toward the natural product itself, a result was obtained that contrasted the model study. The (E)-oxime 3 did not undergo Beckmann rearrangement, but instead an intramolecular Mannich cyclization whereby the electron rich C4 site attacked the intermediate iminum ion, generating the 4-(indolin-2-yl)indole 25 bearing the heterocyclic framework of the slime mould pigment arcyriacyanin A. Although this route did not result in the synthesis of iheyamine A being accomplished, some interesting observations related to the venerable Beckmann rearrangement and Mannich cyclization reactions are described.
- Lindsay, Ashley C.,Sperry, Jonathan
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- Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase
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The vascular endothelial growth factor receptor-2 signaling pathway promotes the formation of new blood vessels, and vascular endothelial growth factor receptor-2 tyrosine kinase exists in both active and inactive conformations. Novel indole–benzimidazole and indole–benzothiazole derivatives joined by different linkers are designed and synthesized as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, HT29, A549, and MDA-MB-435) and human umbilical vein endothelial cell. Meanwhile, the inhibitory activities against vascular endothelial growth factor receptor-2 are estimated in vitro and the binding interactions with dual conformations of vascular endothelial growth factor receptor-2 tyrosine kinase are evaluated by molecular docking. Compounds 5a–c and 14 show inhibitory activity against vascular endothelial growth factor receptor-2 tyrosine kinase and promising cytotoxicity, specifically with IC50 values ranging between 0.1 and 1 μM, which imply broad-spectrum antitumor activity. These results provide a deep insight into potential structural modifications for developing potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
- Ding, Yangyang,Liu, Kai,Zhao, Xinyu,Lv, Yingtao,Yu, Rilei,Kang, Congmin
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p. 286 - 294
(2020/01/28)
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- Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging
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Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme’s aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors. Radiosynthesis of a potential GSK-3β tracer [18F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.
- Hu, Kongzhen,Patnaik, Debasis,Collier, Thomas Lee,Lee, Katarzyna N.,Gao, Han,Swoyer, Matthew R.,Rotstein, Benjamin H.,Krishnan, Hema S.,Liang, Steven H.,Wang, Jin,Yan, Zhiqiang,Hooker, Jacob M.,Vasdev, Neil,Haggarty, Stephen J.,Ngai, Ming-Yu
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supporting information
p. 287 - 292
(2017/03/17)
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- Use of indole compounds in radix isatidis, and derivatives thereof in preparation of anti-influenza virus medicines
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The invention discloses an application of indole compounds extracted from radix isatidis and represented by general formula (I), and derivatives and pharmaceutically acceptable salts thereof in the preparation of anti-influenza virus medicines or healthcare products, and discloses a preparation method of the compounds, and an application of medicinal compositions containing the compounds in the preparation of the anti-influenza virus medicines or healthcare products.
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Paragraph 0514; 0516
(2017/09/21)
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- Indole compound with antivirus activity in radix isatidis and derivative of indole compound
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The invention discloses an indole compound extracted from radix isatidis shown in a general formula (I) and a derivative of the indole compound, as well as a salt acceptable on pharmacy, a preparation method of the compound, and a medicinal composite. The compound has apparent HIV-resisting activity and influenza virus-resisting activity, and can be used for preparing drugs or healthcare products for resisting HIV or influenza viruses. (The formula is shown in the description.).
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Paragraph 0516
(2017/09/29)
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- Design, synthesis and activity evaluation of some novel indole derivatives
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A series of novel indole derivatives as CDK4 inhibitors were designed and synthesized though the condensation reaction between the indolic acid and the corresponding substituted amine. The key step of our synthetic process is the efficient condensation reaction conducted by two different methods. The MTT and kinase assays were conducted used to assess the antitumor activity and cyclin-dependent kinases (CDKs) inhibitory activity. The most active compound 8b has an IC50 of 10-25 μM for the inhibition of four different tumor cells and CDK4. The higher activities of 8b were influenced by more conformational freedom resulted form the non-planar structure and by the stronger hydrogen bonding capability. Thus, the strategy we adapt to design potent, non-toxic CDK4 inhibitors is successful.
- He, Dian,Yang, Zhu-Qing,Hou, Meng
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p. 1729 - 1734
(2015/03/04)
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- Synthesis of new 1,3,4-benzotriazepin-5-one derivatives and their biological evaluation as antitumor agents
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New derivatives of 1,3,4-benzotriazepin-5-one were designed and synthesized as structural analogues to the antitumor agents devazepide and asperlicin. An efficient and novel approach to the synthesis of 2-amino-1,3,4-benzotriazepin-5- one 2 was developed and its structure was confirmed. The newly synthesized derivatives were evaluated for their in vitro antitumor activity on 60 different cell lines. Compounds 8 and 9 displayed the most potent antitumor activity against several cell lines specifically ovarian cancer, renal cancer and prostate cancer, while compounds 5, 10 and 12 showed significant activities against UO-31 renal cancer cell line.
- Taher, Azza T.,Mohammed, Lamia W.
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p. 684 - 693
(2013/07/11)
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- Glyoxyl analogs of indole phytoalexins: Synthesis and anticancer activity
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Glyoxyl analogs of indole phytoalexins brassinin, 1-methoxybrassinin, brassitin, 1-methoxybrassitin and 1-methoxybrassenin B were prepared, using (1H-indol-3-yl)-, (1-methoxyindol- 3-yl)- and [1-(2,3,4,6-tetra-O-acetyl-β- D-glucopyranosyl)indol-3-yl]glyoxyl chlorides as starting compounds. Synthesized products were examined for their antiproliferative activity against human cancer cell lines Jurkat (T-cell acute lymphoblastic leukemia), MCF-7 (breast adenocarcinoma, estrogen receptor-positive), MDA-MB-231 (breast adenocarcinoma, estrogen receptor-negative), HeLa (cervical adenocarcinoma), CCRF-CEM cell line (T-cell acute lymphoblastic leukemia) and A-549 cell line (lung adenocarcinoma), and their activity compared with natural phytoalexins and corresponding (1H-indol-3-yl)acetic acid derivatives. The highest potency with IC50 3.3-66.1 μmol l-1 was found for glyoxyl analogs of 1-methoxybrassenin B.
- Kutschy, Peter,Sykora, Andrej,Curillova, Zuzana,Repovska, Maria,Pilatova, Martina,Mojzis, Jan,Mezencev, Roman,Pazdera, Pavel,Hromjakova, Tatiana
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experimental part
p. 887 - 903
(2011/06/22)
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- Rhodium(II) catalyzed intramolecular insertion of carbenoids derived from 2-pyrrolyl and 3-indolyl α-diazo-β-ketoesters and α-diazoketones
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α-Diazo-β-ketoesters and α-diazoketones derived from 2-pyrrolylacetic, 2-pyrrolylpropionic, 3-indolylacetic and 3-indolylpropionic acids afforded carbenoid derived cyclization products on treatment with catalytic rhodium(II) acetate.
- Cuevas-Ya?ez, Erick,Muchowski, Joseph M.,Cruz-Almanza, Raymundo
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p. 1505 - 1511
(2007/10/03)
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- 3-(Arylacetylamino)-N-methylbenzamides: A novel class of selective anti-Helicobacter pylori agents
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After chemical modification preceded by the random screening of our chemical library, a novel class of selective anti-Helicobacter pylori agents was generated. Consequently, the 3-(arylacetylamino)-N-methylbenzamides, which were quite easy to prepare, showed potent inhibitory activity against Helicobacter pylori but exhibited no inhibitory activity against other sorts of bacteria and fungi, e.g., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacteroides fragilis, and Candida albicans. These compounds showed potent anti-H. pylori activity under acidic conditions, whereas amoxicillin and clarithromycin decreased activity. The 3-(3-arylpropionylamino)-N-methylbenzamides, 3-(aryloxyacetylamino)-N-methylbenzamides, and (3-methylcarbamoylphenyl)carbamic acid 1-arylmethyl esters also exhibited potent anti-H. pylori activity. Finally, we selected 7n (BAS-118) as a candidate compound for further evaluation.
- Ando,Kawamura,Chiba
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p. 4468 - 4474
(2007/10/03)
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- Intramolecular carbenoid insertions: The reactions of α-diazoketones derived from pyrrolyl and indolyl carboxylic acids with rhodium(II) acetate
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α-Diazoketones derived from pyrrolyl- and indolyl-carboxylic acids were prepared and their Rh2(OAc)4 catalyzed decomposition chemistry was studied. These reactions generally resulted in the alkylation of the heteroaromatic system by the ketocarbenoid and in some instances the systems underwent CH or NH insertions. Evidence that some of these reactions proceed via a cyclopropane intermediate is presented. The methodology described provides facile access to fused pyrrolyl- or indolyl-cycloalkanone systems wherein the carbonyl is beta to the heteroaromatic system. (C) 2000 Elsevier Science Ltd.
- Salim, Mohamed,Capretta, Alfredo
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p. 8063 - 8069
(2007/10/03)
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- Antidiabetic agents
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Compounds of formula I: as well as tautomers, pharmaceutically acceptable salts, hydrates, prodrugs and reduced forms are disclosed. The compounds are useful for the treatment and prevention of diabetes mellitus, and in particular, for the treatment or prevention of hyperglycemia in diabetic patients.
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- DIBENZODIAZEPINE ENDOTHELIN ANTAGONISTS
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Endothelin-inhibiting compounds of the formula STR1 wherein: one of R 1 and R 2 is Y 2-CO 2 H and the other is R; R is(a) hydrogen,(b) alkyl, (c) alkenyl,(d) alkynyl,(e) cycloalkyl,(f) cycloalkenyl, (g) aryl, (h) cycloalkylalkyl,(i) cycloalkenylalkyl, or(j) aralkyl; R. sup.3 is aryl or heteroaryl;X 1 and X 2 are each independently (a) hydrogen,(b) halo or haloalkyl,(c) hydroxy,(d) alkoxy(e) cyano, (f) nitro, or (g) amino, alkylamino, or dialkylamino;and the remaining symbols are as defined in the specification.
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- Synthesis of a Novel, Conformationally Restricted Analog of Tryptophan
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The synthesis of a new, conformationally restrained analogue of tryptophan, 1,2,3,4-tetrahydro-2-amino-2-carboxy-cyclopentindole (5) is described.The key step involves the BF3*Et2O catalyzed intramolecular cyclization of α-diazoketone 2b into the 1,2,3,4-tetrahydro-cyclopentindol-2-one (3).Key Words: Conformationally restrained tryptophan analog, diazoketone-BF3*Et2O catalyzed intramolecular cyclization, cycloalkindolones.
- Franceschetti, Luca,Garzon-Aburbeh, Aaron,Mahmoud, Mahmoud R.,Natalini, Benedetto,Pelliciari, Roberto
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p. 3185 - 3188
(2007/10/02)
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- Synthesis of (+/-)-Catharanthine, (+)-Anhydrovinblastine, and (-)-Anhydrovincovaline
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An efficient total synthesis of (+/-)-catharanthine (1) has been accomplished.Diels-Alder reaction of 8 with α-chloroacryloyl chloride followed by reaction with MeOH gave 9.Treatment of 9 with Me3SiI gave 10, and reaction of 10 with indole-3-acetyl chloride provided 11, which was converted to 13.Irradiation of 13 in CH3CN/H2O with a 450-W Hanovia mercury lamp through a Pyrex filter provided 14.Reduction of 14 by treatment with Et3OBF4 and NaBH3CN gave (+/-)-catharanthine (1).The coupling of synthetic (+/-)-catharanthine with natural (-)-vindoline (2) via modified Polonovski reaction provided (+)-anhydrovinblastine (15a) and (-)-anhydrvincovaline (17a), which could be easily separated by flash chromatography.
- Raucher, Stanley,Bray, Brian L.,Lawrence, Ross F.
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p. 442 - 446
(2007/10/02)
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