1477-49-2Relevant academic research and scientific papers
Synthesis and antiproliferative activity of novel heterocyclic indole-trimethoxyphenyl conjugates
Cahill, Michael M.,O’Shea, Kevin D.,Pierce, Larry T.,Winfield, Hannah J.,Eccles, Kevin S.,Lawrence, Simon E.,McCarthy, Florence O.
, (2017)
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.
Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 kinase inhibition
Winfield, Hannah J.,Cahill, Michael M.,O'Shea, Kevin D.,Pierce, Larry T.,Robert, Thomas,Ruchaud, Sandrine,Bach, Stéphane,Marchand, Pascal,McCarthy, Florence O.
, p. 4209 - 4224 (2018)
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.
An efficient synthesis and biological evaluation of novel analogues of natural product Cephalandole A: A new class of antimicrobial and antiplatelet agents
Sharma, Vashundhra,Jaiswal, Pradeep K.,Kumar, Krishan,Saran, Mukesh,Mathur, Manas,Swami, Ajit K.,Chaudhary, Sandeep
, p. 13 - 19 (2018)
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.
Glyoxyl analogs of indole phytoalexins: Synthesis and anticancer activity
Kutschy, Peter,Sykora, Andrej,Curillova, Zuzana,Repovska, Maria,Pilatova, Martina,Mojzis, Jan,Mezencev, Roman,Pazdera, Pavel,Hromjakova, Tatiana
, p. 887 - 903 (2010)
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.
K2S2O8mediated synthesis of 5-Aryldipyrromethanes and meso-substituted A4-Tetraarylporphyrins
Laha, Joydev K.,Hunjan, Mandeep Kaur
, p. 664 - 673 (2021/06/03)
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.
Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids
Long, Lipeng,Wang, Jieyan,Gu, Liuqing,Yang, Shiguang,Qiao, Liang,Luo, Guotian,Chen, Zhengwang
supporting information, p. 12084 - 12092 (2021/08/24)
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.
K2S2O8activation by glucose at room temperature for the synthesis and functionalization of heterocycles in water
Hunjan, Mandeep Kaur,Laha, Joydev K.
supporting information, p. 8437 - 8440 (2021/09/02)
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.
Metal-free benzoylation of imidazoheterocycles by oxidative decarboxylation of arylglyoxylic acids
Jaspal, Sonam,Shinde, Vikki N.,Meena, Neha,Nipate, Dhananjay S.,Rangan, Krishnan,Kumar, Anil
, p. 9072 - 9080 (2020/11/27)
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
Optimization of potent dfg-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics
Horbert, Rebecca,Pinchuk, Boris,Johannes, Eugen,Schlosser, Joachim,Schmidt, Dorian,Cappel, Daniel,Totzke, Frank,Sch?chtele, Christoph,Peifer, Christian
, p. 170 - 182 (2015/03/04)
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.
Sulfur rich 2-mercaptobenzothiazole and 1,2,3-triazole conjugates as novel antitubercular agents
Mir, Fauzia,Shafi, Syed,Zaman,Kalia, Nitin Pal,Rajput, Vikrant S.,Mulakayala, Chaitanya,Mulakayala, Naveen,Khan, Inshad A.,Alam
, p. 274 - 283 (2014/03/21)
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.
