- Investigations regarding the utility of prodigiosenes to treat leukemia
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Prodigiosenes, possessing a 4-methoxypyrrolyldipyrrin skeleton, are known for their anti-cancer activity. Structural modification of the C-ring resulted in a series of prodigiosenes that displayed promising activity against leukemia cell lines during in v
- Smithen, Deborah A.,Forrester, A. Michael,Corkery, Dale P.,Dellaire, Graham,Colpitts, Julie,McFarland, Sherri A.,Berman, Jason N.,Thompson, Alison
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- 5-Substituted pyrido[2,3-d]pyrimidine, an inhibitor against three receptor tyrosine kinases
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NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N′-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 μM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3′-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
- Kammasud, Naparat,Boonyarat, Chantana,Sanphanya, Kingkan,Utsintong, Maleeruk,Tsunoda, Satoshi,Sakurai, Hiroaki,Saiki, Ikuo,André, Isabelle,Grierson, David S.,Vajragupta, Opa
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scheme or table
p. 745 - 750
(2009/09/25)
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- Novel inhibitor for fibroblast growth factor receptor tyrosine kinase
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NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minim
- Kammasud, Naparat,Boonyarat, Chantana,Tsunoda, Satoshi,Sakurai, Hiroaki,Saiki, Ikuo,Grierson, David S.,Vajragupta, Opa
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p. 4812 - 4818
(2008/02/12)
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- Pyrrole-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formulae I and Ia, wherein R0 ; R1 ; R2 ; R3 ; R4; R22, Q; V, G and M have the meanings indicated in the claims. The compounds of the formulae I and Ia are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formulae I and Ia, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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Page/Page column 47
(2008/06/13)
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- Indolinone compounds as kinase inhibitors
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The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds of the invention. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds of the invention and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
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Page/Page column 96
(2010/11/30)
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- Highly Sensitive Fluorescence Probes for Nitric Oxide Based on Boron Dipyrromethene Chromophore - Rational Design of Potentially Useful Bioimaging Fluorescence Probe
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Boron dipyrromethene (BODIPY) is known to have a high quantum yield (φ) of fluorescence in aqueous solution but has not been utilized much for biological applications, compared to fluorescein. We developed 8-(3,4-diaminophenyl)-2,6-bis(2-carboxyethyl)-4,4
- Gabe, Yu,Urano, Yasuteru,Kikuchi, Kazuya,Kojima, Hirotatsu,Nagano, Tetsuo
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p. 3357 - 3367
(2007/10/03)
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- Design, synthesis, and evaluations of substituted 3-[(3- or 4- carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases
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Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain- containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC50 values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC50 values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC50 value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
- Sun, Li,Tran, Ngoc,Liang, Congxin,Tang, Flora,Rice, Audie,Schreck, Randall,Waltz, Kara,Shawver, Laura K.,McMahon, Gerald,Tang, Cho
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p. 5120 - 5130
(2007/10/03)
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- Normal and abnormal heme biosynthesis. 2.1 Synthesis and metabolism of type-III pentacarboxylic porphyrinogens: Further experimental evidence for the enzymic clockwise decarboxylation of uroporphyrinogen-III
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Uroporphyrinogen decarboxylase catalyses the sequential decarboxylation of uroporphyrinogen-III (1) to give coproporphyrinogen-III (2), a precursor to the hemes and chlorophylls. This involves the decarboxylation of four nonequivalent acetate side chains to produce methyl units and in principle could take place by 24 different pathways involving up to 14 intermediary porphyrinogens. In the past, seemingly contradictory data have been presented that either support an ordered 'clockwise' decarboxylation pathway or a random decarboxylation process. Four pentacarboxylate porphyrinogens might be involved immediately before the formation of 2, and these compounds have been synthesized as the corresponding porphyrin pentamethyl esters via tripyrrene and a,c-biladiene intermediates. Hydrolysis of the methyl esters and reduction with 3% sodium amalgam gave the required porphyrinogens, and these were incubated with crude enzyme preparations derived from chicken red cell hemolysates. One of these pentacarboxylate porphyrinogens. (5dab) consistently proved to be a much better substrate than the other three, providing new support for the 'clockwise' pathway for coproporphyrinogen-III formation.
- Lash, Timothy D.,Mani, Ukti N.,Lyons, Elizabeth A.,Thientanavanich, Pornlert,Jones, Marjorie A.
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p. 478 - 487
(2007/10/03)
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- Haem d1: Development of a new coupling procedure leading to the synthesis of isobacteriochlorins
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A new approach has been developed for construction of the western and eastern lactams, e.g. 2 and 3, needed for synthesis of isobacteriochlorins. It involves acylation of pyrroles with lactonic acids to form ketones. These are then efficiently converted into the desired lactams by a short sequence of reactions. All the steps are high yielding and simple to carry out.
- Mackman, Richard L.,Micklefield, Jason,Block, Michael H.,Leeper, Finian J.,Battersby, Alan R.
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p. 2111 - 2122
(2007/10/03)
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- Synthetic and Biosynthetic Studies of Porphyrins. Part 7. The Action of Coproporphyrinogen Oxidase on Coproporphyrinogen-IV: Syntheses of Protoporphyrin-XIII, Mesoporphyrin XIII, and Related Tricarboxylic Porphyrins
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Coproporphyrinogen-IV (2a) is converted by an enzyme system from chicken blood into a tricarboxylic porphyrinogen (2b) and protoporphyrinogen-XIII (2c).The corresponding porphyrins were isolated as their methyl esters (3b) and (3c) and their structures were deduced by mass and n.m.r. spectrometry (including the use of shift reagents).Confirmation of these conclusions was obtained by total synthesis of the new porphyrins by the MacDonald and ac-biladiene routes.The vinyl groups were introduced either via acetoxyethyl side-chains derived from precursor pyrroles, or by reduction and dehydration of acetyl groups inserted into the porphyrins during the final stages of the syntheses.Mesoporphyrin-XIII dimethyl ester (3m) and the ethyl analogue (3n) of the vinyl tripropionate porphyrin (3b) were also synthesized by the MacDonald route.
- Al-Hazimi, Hassan M. G.,Jackson, Anthony H.,Knight, David W.,Lash, Timothy D.
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p. 265 - 276
(2007/10/02)
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