Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

Vogt, Dominik Walter; Wéber, Júlia; Ihlefeld, Katja; Brüggerhoff, Astrid; Proschak, Ewgenij; Stark, Holger

doi:10.1016/j.bmc.2014.07.044

Cited by 38 publications

(24 citation statements)

References 45 publications

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“…Optimization of an initial hit compound produced a potent compound, named C2, which was found to be a novel SK1 inhibitor with an IC 50 of 63 nM, with N 500-fold selectivity over SK2 and selectivity over a panel of 62 lipid and protein kinases [148]. Studies have also investigated analogues of SKI-II [67,149], RB-005 [150], FTY720 [78,136,143,151,152] and SLR080811 [153]. Additionally, analogues of novel compounds extracted from natural products, like the SK2 inhibitor (2S,3S,4R)-Pachastrissamine [154,155] and the low-potency SK1 inhibitor belanocarpol, a dimer of resveratrol, have been reported [156].…”

Section: Other Sk Inhibitorsmentioning

confidence: 99%

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

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Sphingosine kinase (SK) 1 and 2 are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule with a wide array of cellular effects. SK1 and 2 have been shown to be up-regulated in tumours and their genetic ablation or inhibition has been shown to slow tumour growth as well as sensitise cancer cells to chemotherapeutics. The SKs have been extensively studied, with a plethora of inhibitors developed that target the sphingosine-binding pocket of the enzyme, some with nanomolar affinities. Recently, inhibitors targeting the ATP pocket of SK have also been described. Here we discuss the development of these new small molecule SK inhibitors, summarise the recent discovery of off-targets effects of many current SK inhibitors, and provide an overview of the usefulness of these inhibitors as in vitro tools and therapeutic agents.

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Section: Other Sk Inhibitorsmentioning

confidence: 99%

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

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“…The heterocyclic compounds have broad applications including the treatment of hypertension, bacterial and HIV infections, allergies and as antibiotics and ligands for estrogen receptors 3,4 . Beside, these compounds have used as inhibitors against fructose 1,6-bisphosphatase 5 , tumor-associated carbonic anhydrase isoforms hCA IX and hCA XII 6 , sphingosine kinase 7 and evaluation of in vitro anticancer activity 8 . The carbonic anhydrases (CAs, EC 4.2.1.1) are superfamily of metalloenzymes present in Archaea, prokaryotes and eukaryotes, and in all life kingdoms with five genetically distinct families described in various organisms.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Kilicaslan

Arslan

Ruya

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Sulfonamide-bearing thiazole compounds were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 12 synthesized sulfonamide (5a-l) on the hydratase and esterase activities of these isoenzymes (hCA-I and hCA-II) were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. Among them 5b was found to be the most active (IC 50 ¼ 0.35 mM; Ki: 0.33 mM) for hCA I and hCA II.

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“…Also, the 2-aminothiazole-4carboxamide compound was a novel class of inhibitors of serine / threonine protein kinase (CHK1) [12]. In another study, (4 -((4-(4chlorophenyl) -2-thiazolyl) amino) phenol compound at a concentration of 10 µM was a moderate inhibitor (15-25% inhibition) in the experimental conditions for sphingosine kinase [13]. These result was similar like our findings about DMTA which DMTA caused a moderate inhibition (10.58 % inhibition at 500 mg/L).…”

Section: Effect Of 2-amino-4-(chloromethyl)thiazole Hydrochloride On mentioning

confidence: 99%

Determination of Glutathione Reductase Activity Changes Exposed to Some 2-Aminothiazole Derivatives

Karadag

Eroğlu

Kırılmış

2019

Cumhuriyet Science Journal

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In this work, effects of concentrations ranging from 0 to 500 mg/L of some 2-aminothiazole derivatives such as 4,4'-(disulfanediylbis(methylene))bis(thiazol-2-amine) dihyrochloride (DMTA) and 2amino-4-(chloromethyl)thiazole hydrochloride (ACT) on glutathione reductase from baker's yeast (Saccharomyces cerevisiae) (GR) were investigated. With exposure of 25, 50, 100, 250 and 500 mg/L concentrations, % GR activity changes were calculated as-5.29 ;-3.85 ;-2.40 ;-6.73 and-10.58 in DMTA applications, while these changes were calculated as +0.98 ; 0.00 ;-0.49 ;-2.45 and 0.00 in ACT applications, respectively. This work indicated that there was a slight decrease in GR activity with the increase of DMTA concentrations and there was no significant change in GR activity with the increase of ACT concentrations. But according to control activities, no statitistical changes were observed in GR activities with exposure of these 2aminothiazole derivatives (p > 0.05, n=3).

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Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

Cited by 38 publications

References 45 publications

Recent advances in the development of sphingosine kinase inhibitors

Recent advances in the development of sphingosine kinase inhibitors

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Determination of Glutathione Reductase Activity Changes Exposed to Some 2-Aminothiazole Derivatives

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