Rhodanine derivatives as inhibitors of JSP-1

Cutshall, Neil S.; O’Day, Christine; Prezhdo, Marina

doi:10.1016/j.bmcl.2005.05.034

“…Finally, condensation of diacid hydrazide 8 with succinic anhydride or phthalic anhydride in refluxing glacial acetic acid furnished the corresponding imides' analogues 16 and 17, respectively, Chart 4. Both the analytical and spectral data (IR, 1 H-NMR, 13 C-NMR and MS) of all the newly synthesized compounds were in full agreement with the proposed structures.…”

supporting

confidence: 75%

“…

Breast cancer is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding nonmelanoma skin cancers.1) Despite the progress achieved in anticancer therapy about 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465000 will die from the disease.1) Accordingly, novel therapeutic strategies to improve prognosis are urgently needed.It is increasingly apparent that a number of protein tyrosine kinases, specifically epidermal growth factor receptor (EGFR) tyrosine kinase and/or its family members play a critical role in the development and progression of many solid tumors, including breast cancer.2,3) Over-expression of EGFR has been observed in about 70% of breast cancer 4) and is associated with later stages of carcinogenesis 5,6) and is implicated in the development of drug resistance with poor prognosis.7-9) Therefore inhibitors of EGFR kinase activity have emerged as promising new approach to cancer therapy.During the last decade azolidinones heterocycles, particularly imidazolidinones, thiazolidinones and pyrrolidinone have gained special attention as potential lead compounds for novel anticancer agents.10) The antineoplastic properties of azolidinones and related heterocycles are most probably caused by their affinity to different anticancer biotargets, such as extracellular signal-regulated kinases (ERK kinases), 11,12) JNK-stimulating phosphatase-1 (JSP-1) 1, 13) tumor necrosis factor-alpha (TNF-a), 14,15) antiapoptic complex Bcl-X L -BH3 2, 16) integrin a v b 3 receptor 3, 17) etc. (Fig.

…”

mentioning

confidence: 99%

“…10) The antineoplastic properties of azolidinones and related heterocycles are most probably caused by their affinity to different anticancer biotargets, such as extracellular signal-regulated kinases (ERK kinases), 11,12) JNK-stimulating phosphatase-1 (JSP-1) 1, 13) tumor necrosis factor-alpha (TNF-a), 14,15) antiapoptic complex Bcl-X L -BH3 2, 16) integrin a v b 3 receptor 3, 17) etc. (Fig.…”

mentioning

confidence: 99%

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Novel Diphenylamine 2,4'-Dicarboxamide Based Azoles as Potential Epidermal Growth Factor Receptor Inhibitors: Synthesis and Biological Activity

Abou‐Seri

¹

,

Farag

²

,

Hassan

³

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Breast cancer is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding nonmelanoma skin cancers.1) Despite the progress achieved in anticancer therapy about 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465000 will die from the disease.1) Accordingly, novel therapeutic strategies to improve prognosis are urgently needed.It is increasingly apparent that a number of protein tyrosine kinases, specifically epidermal growth factor receptor (EGFR) tyrosine kinase and/or its family members play a critical role in the development and progression of many solid tumors, including breast cancer.2,3) Over-expression of EGFR has been observed in about 70% of breast cancer 4) and is associated with later stages of carcinogenesis 5,6) and is implicated in the development of drug resistance with poor prognosis.7-9) Therefore inhibitors of EGFR kinase activity have emerged as promising new approach to cancer therapy.During the last decade azolidinones heterocycles, particularly imidazolidinones, thiazolidinones and pyrrolidinone have gained special attention as potential lead compounds for novel anticancer agents.10) The antineoplastic properties of azolidinones and related heterocycles are most probably caused by their affinity to different anticancer biotargets, such as extracellular signal-regulated kinases (ERK kinases), 11,12) JNK-stimulating phosphatase-1 (JSP-1) 1, 13) tumor necrosis factor-alpha (TNF-a), 14,15) antiapoptic complex Bcl-X L -BH3 2, 16) integrin a v b 3 receptor 3, 17) etc. (Fig. 1). Recent reports showed that imidazolidinones, and thiazolidinones were found to inhibit the kinase activity of EGFR. Where, some 1-phenethyl-5-(E)-benzylidine hydantoins 4 inhibited EGFR autophosphorylation and polyglutamic acid/ tyrosine (polyGAT) phosphorylation. 18,19) Moreover, a series of hydrazono thiazolidin-4-one 5 that own high antineoplastic activity against breast cancer cells MCF-7 and were potent inhibitors of EGFR autophosphorylation has been repoted. 20) Furthermore, dianilinophthalimide 6 that can bind competitively with the ATP to EGFR showed good selectivity between different tyrosine kinases.21) Therefore, azolidinones are considered good scaffolds for future design of tyrosine kinase inhibitors. In addition, benzamides and bezamidines were synthesized as mimics of the classical EGFR inhibitors 4-anilino-quinazolines.22) Also, we have recently reported preliminary results on antiproliferative action of 2,4Ј-bis-heterocyclic diphenylamine 7 against MCF-7 cell line, that might be mediated through the inhibition EGFR kinase activity. 23)Promoted by these observations and in continuation to the previous work, 23) we designed and synthesized hybrid molecules of diphenylamine-2,4Ј-dicarboxamide (as dibenzamide template) and different azolidinones or related heterocyclic rings 11, 13-17 aiming to obtain highly active antitumor agents, with probable EGFR tyrosine kinase inhibitory activity. The new hybrids were inspired by co...

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“…Thiazolidin-4-one derivatives have been reported for broad spectrum of biological activities such as antioxidant (2), anticancer (3,4), anti-inflammatory (5, 6), antimicrobial (7,8), anti-HIV (9, 10), antiviral (11), anticonvulsant (12,13), and antihypertensive (14) activities. Mechanisms of thiazolidin-4-one and related heterocycles for anticancer activity may be associated with their affinity to anticancer biotargets, such as non-membrane protein tyrosine phosphatase (SHP-2) (15), JNK-stimulating phosphatase-1 (JSP-1) (16) tumor necrosis factor TNF-a (17), antiapoptotic biocomplex Bcl-X L -BH3 (18) and integrin a v b 3 (19), etc. On the other hand, azoles are proven chemotherapeutic agents.…”

mentioning

confidence: 99%

Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones

Joseph¹,

Shah²,

Kumar³

et al. 2013

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Reactive oxygen species (ROS) induced oxidative stress is believed to be a primary causative factor of various inflammatory diseases. ROS has been linked with cancer, coronary heart disease, and neurodegenerative diseases, and their presence in the body causes damage to the DNA of cells. Antioxidants exert their effects by scavenging or preventing the generation of ROS, which can protect the formation of free radicals and retard the progress of many chronic diseases, including cancer, inflammation, and car- A series of novel 5-alkyl/aryl thiadiazole substituted thiazolidin-4-ones were synthesized by a two-step process. In the first step, 5-alkyl/aryl substituted 2-aminothiadiazoles were synthesized, which on reaction with substituted aromatic aldehydes and thioglycolic acid in the presence of dicyclohexylcarbodiimide afforded thiazolidin-4-ones. All the compounds were synthesized in fairly good yields and their structures were confirmed by spectral and physical data. The title compounds were screened for in vitro anti-proliferative activity on human breast adenocarcinoma cells (MCF-7) by MTT assay. Most of the derivatives showed an IC 50 less than 150 µmol L -1 . Among the compounds tested, 2-(2-nitrophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3f), 2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2--yl)-thiazolidin-4-one (3b), and 2-(4-chlorophenyl)-3--(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3c) were found to be the most active derivatives with IC 50 values of 46.34, 66.84, and 60.71 µmol L -1 , respectively. Antioxidant studies of all the synthesized compounds were carried out by diphenylpicrylhydrazyl (DPPH) assay. Among the compounds tested, 2-phenyl-3-(5-styryl--1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3s) elicited superior antioxidant activity with IC 50 of 161.93 µmol L -1 .

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“…The micromolar activity of the two rhodanine compounds was confirmed in two different assay formats. Compounds similar to the structure of CCT021812 have been shown to be inhibitors of the phosphatase JSP-1 15 and their activity ascribed to the ability of the C=C bond to act as a Michael acceptor. This does not seem to be the case with CCT021812 at least, since its activity was approximately the same in the absence and presence of DTT.…”

Section: Hit Compoundsmentioning

confidence: 99%

Small-Molecule Inhibitors of the Protein Methyltransferase SET7/9 Identified in a High-Throughput Screen

Francis

¹

,

Rowlands

²

,

Workman

³

et al. 2012

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Aberrant expression of chromatin-modifying enzymes (CMEs) is associated with a range of human diseases, including cancer. CMEs are now an important target area in drug discovery. Although the role that histone and protein (lysine) methyltransferases (PMTs) play in the regulation of transcription and cell growth is increasingly recognized, few smallmolecule inhibitors of this class of enzyme have been reported. Here we describe an assay suitable for primary compound screening for the identification of PMT inhibitors. The assay followed the methylation of histones in the presence of the PMT SET7/9 and the radioactive cofactor S-adenosyl-methionine using scintillating microplates (FlashPlate) and was used to screen approximately 65 000 compounds (% coefficient of variation = 10%; Z′ = 0.6). The hits identified from a library of more than 63 000 diverse small molecules included a series of rhodanine compounds with micromolar activity. A screen of the National CancerInstitute Diversity Set (2000 compounds) identified an orsein derivative that inhibited SET7/9 (~20 µM) and showed modest growth inhibition associated with the expected cellular phenotype of reduced histone methylation in a human tumor cell line. The assay represents a useful tool for the identification of inhibitors of PMT activity.

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Rhodanine derivatives as inhibitors of JSP-1

Cited by 181 publications

References 25 publications

Novel Diphenylamine 2,4'-Dicarboxamide Based Azoles as Potential Epidermal Growth Factor Receptor Inhibitors: Synthesis and Biological Activity

Novel Diphenylamine 2,4'-Dicarboxamide Based Azoles as Potential Epidermal Growth Factor Receptor Inhibitors: Synthesis and Biological Activity

Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones

Small-Molecule Inhibitors of the Protein Methyltransferase SET7/9 Identified in a High-Throughput Screen

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