- Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates
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The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.
- Cahill, Michael M.,O’Shea, Kevin D.,Pierce, Larry T.,Winfield, Hannah J.,Eccles, Kevin S.,Lawrence, Simon E.,McCarthy, Florence O.
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- Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition
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Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.
- Winfield, Hannah J.,Cahill, Michael M.,O'Shea, Kevin D.,Pierce, Larry T.,Robert, Thomas,Ruchaud, Sandrine,Bach, Stéphane,Marchand, Pascal,McCarthy, Florence O.
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- An efficient synthesis and biological evaluation of novel analogues of natural product Cephalandole A: A new class of antimicrobial and antiplatelet agents
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Cephalandole A 2, a small indole alkaloid isolated from the Taiwanese orchid Cephalanceropsis gracilis (Orchidaceae), exhibits anticancer activity. Surprisingly, this natural product has not been evaluated for any other biological activity so far. To discover other novel potential of Cephalandole A 2, an efficient and economic synthetic protocol for novel Cephalandole A analogues 21a-o has been developed, in only 3 steps from using indole, and applied for their biological activity. Biological testing showed that Cephalandole A 2 and its novel analogues 21a-o exhibited potential antimicrobial and antiplatelet activity in preliminary assay. To the best of our knowledge, this is the first report of Cephalandole A 2 and its novel synthetic analogues 21a-o as a new class of antimicrobial and antiplatelet agents. In this study, 2 and other analogues i.e., 21b, 21d, 21i and 21o showed promising antimicrobial activity against the phytopathogenic bacteria and fungi. Cephalandole A 2, 21c, 21f and 21i, also showed potent antiplatelet activity.
- Sharma, Vashundhra,Jaiswal, Pradeep K.,Kumar, Krishan,Saran, Mukesh,Mathur, Manas,Swami, Ajit K.,Chaudhary, Sandeep
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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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- K2S2O8mediated synthesis of 5-Aryldipyrromethanes and meso-substituted A4-Tetraarylporphyrins
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The synthesis of dipyrromethanes from pyrrole and arylglyoxylic acids in the presence of K2S2O8at 90 C is reported affording dipyrromethanes in very good yields. Unlike an excess pyrrole traditionally used in dipyrromethane synthesis, the current method uses a stoichiometric amount of pyrrole avoiding any use of Br?nsted or Lewis acid. A gram scale synthesis of 5-phenyldipyrromethane is also achieved demonstrating potential scale up of dipyrromethanes using this method feasible. Subsequently, dipyrromethanes were converted to A4tetraarylporphyrins also in the presence of K2S2O8at 90C. A direct synthesis of A4-tetraphenylporphyrin from excess pyrrole and phenylglyoxylic acid in the presence of K2S2O8 at 90C is also reported.
- Laha, Joydev K.,Hunjan, Mandeep Kaur
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p. 664 - 673
(2021/06/03)
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- Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids
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A novel catalyst-free radical oxidative C-H annulation reaction of arylamines with α-keto acids toward benzoxazin-2-ones synthesis under mild conditions was developed. This hypervalent iodine(III)-promoted process eliminated the use of a metal catalyst or additive with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a radical initiator for this reaction. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A.
- Long, Lipeng,Wang, Jieyan,Gu, Liuqing,Yang, Shiguang,Qiao, Liang,Luo, Guotian,Chen, Zhengwang
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supporting information
p. 12084 - 12092
(2021/08/24)
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- K2S2O8activation by glucose at room temperature for the synthesis and functionalization of heterocycles in water
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While persulfate activation at room temperature using glucose has primarily been focused on kinetic studies of the sulfate radical anion, the utilization of this protocol in organic synthesis is rarely demonstrated. We reinvestigated selected K2S2O8-mediated known organic reactions that invariably require higher temperatures and an organic solvent. A diverse, mild functionalization and synthesis of heterocycles using the inexpensive oxidant K2S2O8 in water at room temperature is reported, demonstrating the sustainability and broad scope of the method. Unlike traditional methods used for persulfate activation, the current method uses naturally abundant glucose as a K2S2O8 activator, avoiding the use of higher temperature, UV light, transition metals or bases.
- Hunjan, Mandeep Kaur,Laha, Joydev K.
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supporting information
p. 8437 - 8440
(2021/09/02)
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- Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids
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A simple and straightforward approach has been realized for the direct benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids in the presence of K2S2O8 as an oxidant. Various functional groups were tolerated on both imidazoheterocycles and arylglyoxylic acids and a wide range of C5-benzoyl-imidazoheterocycles were obtained in good to high yields (50-84%). Radical trapping experiments confirmed the involvement of the radical pathway. The developed protocol is amenable for a scale-up reaction. This journal is
- Jaspal, Sonam,Shinde, Vikki N.,Meena, Neha,Nipate, Dhananjay S.,Rangan, Krishnan,Kumar, Anil
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p. 9072 - 9080
(2020/11/27)
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- Optimization of potent dfg-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics
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In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC50 = 0.5 μM). Furthermore, 2 was shown to be selective for PDGF-Rβ in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rβ homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 μM in a PDGF-Rβ enzymatic assay also showing activity against PDGF-R dependent cancer cells.
- Horbert, Rebecca,Pinchuk, Boris,Johannes, Eugen,Schlosser, Joachim,Schmidt, Dorian,Cappel, Daniel,Totzke, Frank,Sch?chtele, Christoph,Peifer, Christian
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p. 170 - 182
(2015/03/04)
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- Sulfur rich 2-mercaptobenzothiazole and 1,2,3-triazole conjugates as novel antitubercular agents
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A series of benzfused heterocyclic derivatives such as amide conjugates of 2-(benzo[d]thiazol-2-ylthio)acetic acid with aromatic/aliphatic/cyclic secondary amines (5a-5o & 8a-8m); 1,2,3-triazole conjugates of 2- mercaptobenzothiazoles and amide conjugates of indole-3-glyoxalic acid with cyclic secondary amines (14a-14g) have been synthesized and were screened for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth microdilution assay method. Compounds 8b, 8f, 8g and 8l inhibited the growth of the H37Rv strain at concentrations of 8 μg/mL. These compounds (8b, 8f, 8g and 8l) have been further identified as bactericidal and are completely killing the microbes at 32-64 μg/mL concentrations. Molecular docking studies of the active compounds reveal that these compounds are targeting DprE1 and may act as DprE1 inhibitors.
- Mir, Fauzia,Shafi, Syed,Zaman,Kalia, Nitin Pal,Rajput, Vikrant S.,Mulakayala, Chaitanya,Mulakayala, Naveen,Khan, Inshad A.,Alam
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p. 274 - 283
(2014/03/21)
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- Dissecting metabolic puzzles through isotope feeding: A novel amino acid in the biosynthetic pathway of the cruciferous phytoalexins rapalexin A and isocyalexin A
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Understanding defence pathways of plants is crucial to develop disease-resistant agronomic crops, an important element of sustainable agriculture. For this reason, natural plant defenses such as phytoalexins, involved in protecting plants against microbial pathogens, have enormous biotechnological appeal. Crucifers are economically important plants, with worldwide impact as oilseeds, vegetables of great dietetic value and even nutraceuticals. Notably, the intermediates involved in the biosynthetic pathways of unique cruciferous phytoalexins such as rapalexin A and isocyalexin A remain unknown. Toward this end, using numerous perdeuterated compounds, we have established the potential precursors of these unique phytoalexins and propose for the first time their detailed biosynthetic pathway. This pathway involves a variety of intermediates and a novel amino acid as the central piece of this complex puzzle. This work has set the stage for the discovery of enzymes and genes of the biosynthetic pathway of cruciferous phytoalexins of unique scaffolds.
- Pedras, M. Soledade C.,Yaya, Estifanos E.
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p. 1149 - 1166
(2013/03/29)
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- Effective synthesis of 3,5-diaryl-(1H)-pyrazin-2-ones via microwave mediated ring closure
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In this study we report on a flexible straight forward synthesis toward novel 3,5-diaryl-(1H)-pyrazin-2-ones. Our synthetic strategy involved an acyclic di-keto derivative as key intermediate. The final pyrazin-2-one ring closure reaction was yield-optimized by using a microwave mediated procedure and ammoniumacetate as nitrogen source. Our method is a suitable alternative to palladium-catalyzed coupling reactions for the 3,5-diaryl decoration of the (1H)-pyrazin-2-one scaffold. Since the (1H)-pyrazin-2-ones is present as scaffold in a number of biologically active compounds the reported synthetic platform is a useful approach to generate a set of highly diverse 3,5-diaryl-(1H)-pyrazin-2-one compounds.
- Johannes, Eugen,Horbert, Rebecca,Schlosser, Joachim,Schmidt, Dorian,Peifer, Christian
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p. 4067 - 4072
(2013/07/26)
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- Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation-cyclization cascade
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An enantioselective arylation-cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products.
- Zhu, Shaolin,MacMillan, David W. C.
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supporting information; experimental part
p. 10815 - 10818
(2012/08/07)
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- Synthetic analogs of indole-containing natural products as inhibitors of sortase A and isocitrate lyase
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Guided by the inhibitory activities of indole-containing natural products against isocitrate lyase (ICL) from Candida albicans and sortase A (SrtA) from Staphylococcus aureus, a series of compounds structurally analogous to natural products were synthesized. Eight SrtA inhibitors and an ICL inhibitor having higher activities than the natural products were discovered by screening the enzyme inhibitory activities of synthesized compounds. Among the SrtA inhibitors discovered, six exhibited higher activities than p-hydroxymercuribenzoic acid, which suggests that these compounds have great potential as alternative antibacterial agents.
- Lee, Yeon-Ju,Han, Yu-Ri,Park, Wanki,Nam, Seo-Hee,Oh, Ki-Bong,Lee, Hyi-Seung
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scheme or table
p. 6882 - 6885
(2010/12/24)
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- TRIAZINE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC APPLICATION THEREOF
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The invention relates to triazine derivatives of general formula (I): Wherein R1, R2 and R3 are as defined herein. The invention also relates to a method for preparing these triazine derivatives and to the therapeutic application thereof.
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Page/Page column 12
(2008/06/13)
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- A new facile method for preparation of heterocyclic α-iminonitriles and α-oxoacetic acid from heterocyclic aldehydes, p-aminophenol, and sodium cyanide
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Very efficient, simple, and high yield procedures for the transformation of heterocyclic aldehydes into heterocyclic methylidene-p-hydroxyanilines, heterocyclic α-iminonitriles, and finally into heterocyclic α-oxoacetic acids were described. Considering that many of these compounds have biological activity, the synthetic methodology was optimized using readily available, inexpensive starting materials, and the purification of the product involved only simple crystallization.
- Jursic, Branko S.,Douelle, Frederic,Bowdy, Katherine,Stevens, Edwin D.
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p. 5361 - 5365
(2007/10/03)
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- Alboinon, an oxadiazinone alkaloid from the ascidian Dendrodoa grossularia
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The ascidian Dendrodoa grossularia, collected in the Baltic Sea, contains the new 1,3,5-oxadiazin-2-one alkaloid alboinon (1).
- Bergmann, Tanja,Schories, Dirk,Steffan, Bert
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p. 2055 - 2060
(2007/10/03)
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- A convenient method for the synthesis of indole-3-acetic acids
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Starting from the corresponding indoles, indole-3-acetic acids were synthesized through indole-3-glyoxylic acids, followed by hydrazone formation with p-toluenesulfonhydrazide, then reduction of the hydrazones with sodium borohydride.
- Guan, Xiangming,Borchardt, Ronald T.
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p. 3013 - 3016
(2007/10/02)
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- Process for preparation of tryptophols
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A process for preparing tryptophol derivatives comprises reducing a 3-indolylglyoxylic acid ester or acid halide using an alkali metal borohydride in the presence of an alcohol or ether solvent. The tryptophol derivatives prepared are useful as intermediates to pharmacologically active compounds.
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