The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold

Graczyk, Piotr; Khan, Afzal; Bhatia, Gurpreet S.; Palmer, Vanessa H.; Medland, Darren; Numata, Hirotoshi; Oinuma, Hitoshi; Catchick, Jacqueline; Dunne, Angela; Ellis, Moira V.; Smales, Caroline; Whitfield, Jonathan R.; Neame, Stephen J.; Shah, Bina; Wilton, Daniel K.; Morgan, Louise; Patel, Toshal R.; Chung, Raymond; Desmond, H.; Staddon, James M.; Sato, Nobuaki; Inoue, Atsushi

doi:10.1016/j.bmcl.2005.07.076

Cited by 51 publications

(30 citation statements)

References 34 publications

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“…In contrast, the loss of either JNK1 or JNK2 alone has no serious consequences. JNK3 has therefore been considered to be the most proapoptotic member of the family in the context of neurodegeneration and is currently being targeted for the design of neuroprotective drugs (14,34).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Histone Deacetylase-Related Protein

Morrison

Majdzadeh

Zhang

et al. 2006

Molecular and Cellular Biology

156

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Apoptosis is an essential aspect of normal nervous system development, but when aberrantly activated, apoptosis leads to undesirable neuronal death, and such inappropriate neuronal loss is the hallmark of a variety of neurodegenerative diseases and neurological conditions, such as stroke or traumatic brain injury. The mechanisms underlying the regulation of apoptosis are beginning to be understood. Among the molecules that have recently been implicated are the histone deacetylases (HDACs). HDACs are the catalytic subunits of multiprotein complexes that deacetylate histones (11,42). The action of HDACs is opposed by histone acetyltransferases (HATs) such as CREB-binding protein and p300, which catalyze the transfer of an acetyl moiety from acetyl-coenzyme A to specific lysine residues of histones (25). Acetylation of histones relaxes the chromatin structure to a state that is transcriptionally active, while histone deacetylation transforms chromatin to a transcriptionally repressed state (25). Hence, gene expression is regulated, in part, by the balance of HDAC and HAT activities. Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs and HATs regulate the acetylation of a number of other nonhistone proteins, such as p53, p65/RelA, E2F1, GATA1, and MyoD, suggesting complex functions of HDACs in different cellular processes (11,42). Precisely which cellular functions are involved is currently the subject of intense investigation.Vertebrates express at least 18 distinct HDACs, which have been grouped into three classes based on their similarities with Saccharomyces cerevisiae HDACs (11,42 Class I HDACs consist of little more than a deacetylase domain and function as transcriptional repressors. They generally are nuclear proteins expressed in most tissue and cell types (11,42). On the other hand, members of the class II HDAC subfamily display cell type-restricted patterns of expression and contain a large extended N-terminal extension with which a variety of signaling proteins interact, including MEF2, HP1␣, Bcl6, CtBP, calmodulin,42). Phosphorylation of conserved serine residues in class II HDACs by calcium/calmodulin-dependent kinase (CaMK) or protein kinase D in response to specific stimuli creates docking sites for the 14-3-3 family of protein chaperones (11,28,31,42). Binding of 14-3-3 results in the export of these HDACs from the nucleus and disrupts their interactions with transcriptional corepressor proteins, resulting in derepression of their target genes.Several classes of small-molecule HDAC inhibitors have been identified (11,29 (11,29). Because of their ability to induce the death of transformed cells, HDAC inhibitors are in clinical trials for the treatment of cancers. It is noteworthy, however, that while there are small differences in the sensitivities of individual class I and class II HDACs to different inhibitors, most of the commonly used inhibitors inhibit all HDACs efficiently. The significance of individual HDACs in any biological effect ha...

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Section: Discussionmentioning

confidence: 99%

Neuroprotection by Histone Deacetylase-Related Protein

Morrison

Majdzadeh

Zhang

et al. 2006

Molecular and Cellular Biology

156

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“…Our interest in this area was initiated by sundry reports, 8,[15][16][17] mainly in the patent literature, 18 describing the reaction of the cyclic amidine 3,4-dihydro-2H-pyrrol-5-amine (variously referred to as '2-iminopyrrolidine' and '2-aminopyrroline') (12) with a 2-haloketone. Although the majority of these reports concur that the products are 2-substituted 6,7-dihydro-5H-pyrrolo- Based on studies referred to above, and ignoring any influence that the ring structure may exert, one might expect 12 and 15 to exist predominantly in the imino forms, 12-imino and 15-imino, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in one instance, 8 such an intermediate salt was isolated before completion of the ring closure in a second step.…”

Section: Methodsmentioning

confidence: 99%

Cyclic amidines as precursors for imidazoles

Stevens¹,

Różycka‐Sokołowska²,

Andersson³

et al. 2015

Arkivoc

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The regioselective nucleophilic reactivity of cyclic amidines is considered in the context of their reactions with 2-haloketones to generate imidazoles. Since the tautomer with an endocyclic imine is favoured, reaction with the 2-haloketone electrophile proceeds via initial alkylation at the ring nitrogen. This was confirmed by repeating a suitable literature reaction and submitting the isolated product to single-crystal X-ray analysis.

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“…2-imidazolines have been investigated as antihyperglycemic, anti-inflammatory, antihypertensive, antihypercholesterolemic, and antidepressant reagents [6,7].The imidazole nucleus appears in a number of naturally occurring products among which, the most important are the amino acid, histidine , the purines which comprise many of the important bases in nucleic acids and hydration which occurs in beet sap. Also, In recent years, different imidazole and benzoimidazole drugs have been found to be associated with several biological activities such as antiparasitic, antifungal, anti-inflammatory, antibacterial activities [8], [9]. imidazole derivatives are reported to exhibit a wide range of pharmaceutical bactericidal [8] activities.…”

Section: Introductionmentioning

confidence: 99%

“…Also, In recent years, different imidazole and benzoimidazole drugs have been found to be associated with several biological activities such as antiparasitic, antifungal, anti-inflammatory, antibacterial activities [8], [9]. imidazole derivatives are reported to exhibit a wide range of pharmaceutical bactericidal [8] activities. 5-nitroimidazole (azomycine) is active against infections associated with anaerobic conditions.…”

Section: Introductionmentioning

confidence: 99%

Isotopic exchange method for preparation of io-dine-125-n-(1-p-nitrobenzaldhydephenyl)-2- (2-iodophenyl)-4-(4-nitrobenzilidene)-imidazolin -5-one and its biological evaluation

Labib

2014

International Journal of Basic and Applied Sciences

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N-(1-p-nitrobenzaldhydephenyl)-2-(2-iodophenyl)-4-(4-nitrobenzilidene)-imidazolin-5-onewas labeled with radioactive iodine-125.via nucleophilic substitution reaction, the isotopic exchange labeling process was carried out in dry state at 330oC for 20 min. The radiochemical yield was determined by using electrophoresis and the yield is equal to 93%.Ammonium sulphate was used as catalyst to facilitate the exchange reaction in melt state. Maximum heated with iodine-125 at 330oC for 20 min in a reaction mixture with pH between 6 and 8. The results referred to the importance of use NaOH in a molarity of less than 0.02M to prevent the decomposition of the produced tracer due to the change in pH of the reaction mixture. The biodistrubution pattern of the labeled compound was examined in normal as well as in tumor bearing mice and the data show high clearance from the blood as the activity remind in the blood 11.2% at 4 hours post injection. The labeled compound was extracted via liver as the accumulated activity in the liver and intestine were 14.4, 15.4% respectively at 4 hours post injection The biodistrubution of labeled compound in tumor bearing mice accumulation in ascites with high percentage equal to 55.3 % at 24 hours post injection. This demonstrate the ability of this tracer concentrate in tumor site which primate its possible application as therapeutic agent.

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The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold

Cited by 51 publications

References 34 publications

Neuroprotection by Histone Deacetylase-Related Protein

Neuroprotection by Histone Deacetylase-Related Protein

Cyclic amidines as precursors for imidazoles

Isotopic exchange method for preparation of io-dine-125-n-(1-p-nitrobenzaldhydephenyl)-2- (2-iodophenyl)-4-(4-nitrobenzilidene)-imidazolin -5-one and its biological evaluation

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