Rhodaninecarboxylic acids as novel inhibitors of histoneacetyltransferases

Furdas, Silviya D.; Shekfeh, Suhaib; Kannan, Srinivasaraghavan; Sippl, Wolfgang; Jung, Manfred

doi:10.1039/c2md00211f

Cited by 28 publications

(27 citation statements)

References 44 publications

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“…To investigate the selectivity of ML302/ML302F for bacterial MBLs we tested the activity against TEM-1 (a Class A SBL), PBP-5 (penicillin-binding protein 5 or dacA), PBP-6 (penicillin-binding protein 6, or dacC) from E. coli, hHAT (human histone acetyltransferase), and hHDAC (human histone deacetylase). TEM-1, PBP-5 and -6 and hHAT are known to be inhibited by rhodanines 12,13,31 as are human metallo enzymes hACE-2 (angiotensin converting enzyme 2) and hHAGH (hydroxyacylglutathione hydrolase, human glyoxylase II which is an MBL fold zinc dependent hydrolase). Only in the case of hACE-2 did we observe inhibition (∼75% residual activity at 100 µM) by ML302 but not by ML302F.…”

Section: Resultsmentioning

confidence: 99%

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

et al. 2014

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The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in β-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.

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Section: Resultsmentioning

confidence: 99%

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

et al. 2014

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“…TLC: Rf = 0.39 (hexane:ethyl acetate 7:3 v/v); IR (ATR) ν max / cm -1 2925, 1733, 1372, 759; 1 H and 13 C NMR data were compared with the literature. 33…”

Section: Synthesis Of the Compounds 4h-4lmentioning

confidence: 99%

Identifying New Isatin Derivatives with GSK-3β Inhibition Capacity through Molecular Docking and Bioassays

Britto¹,

Francisco²,

Ferreira³

et al. 2020

J. Braz. Chem. Soc.

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The semi-synthesis of 11 isatin derivatives was achieved through bimolecular nucleophilic substitution and click chemistry. Seven new compounds were obtained. All chemical structures were determined by infrared spectroscopy (IR), nuclear magnetic resonance spectrometry (NMR) and high-resolution mass spectrometry (HRMS) data. These derivatives were evaluated for their anti-GSK-3β activity and all isatin derivatives (N-alkyl and 1,2,3-triazolic) exhibited strong inhibitory activity, with 2b and 4h exhibiting remarkable potency. In addition, docking studies were performed with 2b and 2e models to unravel the molecular mechanism underlying the polar interactions on the GSK-3β ATP-binding site. Scheme 1. (i) Potassium carbonate, dimethylformamide or acetone; (ii) commercial bromide, r.t.

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“…12 The PCAF recombinant catalytic domain used for testing was prepared according to the published protocol for bacterial overexpression of the His-tagged fusion protein. 17 Gcn5 (KAT2A) (n ¼ 2) was purchased from BPS Bioscience (catalog # 50070, San Diego, USA), CBP (KAT3A) (n ¼ 2) from Biomol (catalog # SE-452, Hamburg, Germany), p300 (KAT3B) (n ¼ 2) from BPS Bioscience (catalog # 50071, San Diego, USA). 12 DMSO was used as solvent control.…”

Section: Histone Acetyltransferase Assaysmentioning

confidence: 99%

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

et al. 2014

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Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure-activity studies of pyrido-and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained.While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells.

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Rhodaninecarboxylic acids as novel inhibitors of histoneacetyltransferases

Abstract: Virtual screening has identified rhodanine containing carboxylic acids as new inhibitors of histone acetyltransferases.

Cited by 28 publications

References 44 publications

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Identifying New Isatin Derivatives with GSK-3β Inhibition Capacity through Molecular Docking and Bioassays

Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

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