- COMPOSITIONS AND METHODS FOR ACTIVATING PYRUVATE KINASE
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Provided herein are compositions and methods for activating pyruvate kinase (e.g., in a subject). In particular, provided herein are compositions and methods for treating a disease or condition (e.g., eye disease, blood disorders, or cancer) using pyruvate kinase activators.
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Page/Page column 51-52; 68
(2022/02/05)
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- Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach
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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ~1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.
- Preti, Delia,Romagnoli, Romeo,Rondanin, Riccardo,Cacciari, Barbara,Hamel, Ernest,Balzarini, Jan,Liekens, Sandra,Schols, Dominique,Estévez-Sarmiento, Francisco,Quintana, José,Estévez, Francisco
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p. 1225 - 1238
(2018/09/04)
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- Design of C3-Alkenyl-Substituted 2-Indolylmethanols for Catalytic Asymmetric Interrupted Nazarov-Type Cyclization
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The C3-alkenyl-substituted 2-indolylmethanols have been designed as a new class of substrates for catalytic asymmetric interrupted Nazarov-type cyclizations. In the presence of chiral phosphoric acid as a mild chiral Br?nsted acid, the interrupted Nazarov
- Wang, Cong-Shuai,Wu, Jia-Le,Li, Can,Li, Lin-Zhi,Mei, Guang-Jian,Shi, Feng
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supporting information
p. 846 - 851
(2018/03/06)
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- Discovery of 3-Substituted 1H-Indole-2-carboxylic Acid Derivatives as a Novel Class of CysLT1 Selective Antagonists
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The indole derivative, 3-((E)-3-((3-((E)-2-(7-chloroquinolin-2yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)-7-methoxy-1H-indole-2-carboxylic acid (17k), was identified as a novel and highly potent and selective CysLT1 antagonist with IC50 values of 0.0059 ± 0.0011 and 15 ± 4 μM for CysLT1 and CysLT2, respectively.
- Chen, Huayan,Yang, Hui,Wang, Zhilong,Xie, Xin,Nan, Fajun
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supporting information
p. 335 - 339
(2016/03/25)
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- Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity
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Methuosis is a form of nonapoptotic cell death characterized by an accumulation of macropinosome-derived vacuoles with eventual loss of membrane integrity. Small molecules inducing methuosis could offer significant advantages compared to more traditional anticancer drug therapies that typically rely on apoptosis. Herein we further define the effects of chemical substitutions at the 2-and 5-indolyl positions on our lead compound 3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propene-1-one (MOMIPP). We have identified a number of compounds that induce methuosis at similar potencies, including an interesting analogue having a hydroxypropyl substituent at the 2-position. In addition, we have discovered that certain substitutions on the 2-indolyl position redirect the mode of cytotoxicity from methuosis to microtubule disruption. This switch in activity is associated with an increase in potency as large as 2 orders of magnitude. These compounds appear to represent a new class of potent microtubule-active anticancer agents.
- Trabbic, Christopher J.,Overmeyer, Jean H.,Alexander, Evan M.,Crissman, Emily J.,Kvale, Heather M.,Smith, Marcie A.,Erhardt, Paul W.,Maltese, William A.
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p. 2489 - 2512
(2015/03/30)
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- Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies
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We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
- Thanigaimalai, Pillaiyar,Konno, Sho,Yamamoto, Takehito,Koiwai, Yuji,Taguchi, Akihiro,Takayama, Kentaro,Yakushiji, Fumika,Akaji, Kenichi,Chen, Shen-En,Naser-Tavakolian, Aurash,Sch?n, Arne,Freire, Ernesto,Hayashi, Yoshio
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p. 372 - 384
(2013/10/01)
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- An efficient synthesis of LipidGreen and its derivatives via microwave assisted reaction and their live lipid imaging in zebrafish
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We have developed an efficient synthesis of LipidGreen. The conversion is achieved by selective methylation with trimethylsilyldiazomethane, selective deprotection by BBr3 and an improved microwave-assisted C-allylation procedure. Using this ro
- Pagire, Haushabhau S.,Chun, Hang-Suk,Bae, Myung Ae,Ahn, Jin Hee
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p. 3039 - 3044
(2013/03/29)
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- Synthesis of a new fluorescent small molecule probe and its use for in vivo lipid imaging
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A new small molecule probe for in vivo lipid imaging, LipidGreen (compound 5), was developed. LipidGreen stained lipid droplets in 3T3L1 cell lines and fat deposits in zebrafish without apparent toxicity up to 100 μM. The utility of LipidGreen as a drug s
- Lee, Jae Hong,So, Ju-Hoon,Jeon, Jong Hyun,Choi, Eun Bok,Lee, Yu-Ri,Chang, Young-Tae,Kim, Cheol-Hee,Bae, Myung Ae,Ahn, Jin Hee
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p. 7500 - 7502
(2011/08/07)
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- Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: Structure-activity relationships for cytotoxicity and antitumor activity
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A large number of aziridinyl quinones represented by series 1-9 were studied with respect to their DT-diaphorase substrate activity, DNA reductive alkylation, cytostatic/cytotoxic activity, and in vivo activity. As a result, generalizations have been made with respect with respect to the following: DT-diaphorase substrate design, DT-diaphorase-cytotoxicity quantitative structure-activity relationship (QSAR), and DNA reductive alkylating agent design. A saturating relationship exists between the substrate specificity for human recombinant DT-diaphorase and the cytotoxicity in the human H460 non-small-cell lung cancer cell line. The interpretation of this relationship is that reductive activation is no longer rate-limiting for substrates with high DT-diaphorase substrate specificities. High DT-diaphorase substrate specificity is not desirable in the indole and cylopent[b]indole systems because of the result is the loss of cancer selectivity along with increased toxicity. We conclude that aziridinyl quinones of this type should possess a substrate specificity (Vmax/KM) -4 s-1 for DT-diaphorase in order not to be too toxic or nonselective. While some DNA alkylation was required for cytostatic and cytotoxic activity by series 1-9, too much alkylation results in loss of cancer selectivity as well as increased in vivo toxicity. Indeed, the most lethal compounds are the indole systems with a leaving group in the 3α-position (like the antitumor agent EO9). We conclude that relatively poor DNA alkylating agents (according to our assay) show the lowest toxicity with the highest antitumor activity.
- Skibo,Xing,Dorr
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p. 3545 - 3562
(2007/10/03)
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- A concise synthesis of 3-hydroxyindole-2-carboxylates by a modified Baeyer-Villiger oxidation
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Indole-2-carboxylates are converted in good yields to 3-hydroxyindole-2-carboxylates by use of a Vilsmeier-Haack/Baeyer-Villiger reaction sequence. A systematic examination of the various indole substituents revealed this route to be general in scope. (C) 2000 Published by Elsevier Science Ltd.
- Hickman,Sturino,Lachance
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p. 8217 - 8220
(2007/10/03)
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