Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Thompson, Mark J.; Louth, Jennifer; Ferrara, Steven; Sorrell, F.J.; Irving, Benjamin J.; Cochrane, Edward J.; Meijer, Anthony J. H. M.; Chen, Beining

doi:10.1002/cmdc.201000383

Cited by 25 publications

(21 citation statements)

References 40 publications

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“…Compound 3 was synthesized based upon the synthetic scheme (Scheme 1), in which indole was treated dropwise with chloroacetylchloride in the presence of pyridine for an hour at 60 °C in dioxane to give 2-chloro-1-(1H-indol-3-yl)ethanone ( 7 ), with a yield of 50% [17].…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

et al. 2019

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Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

et al. 2019

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“…[50] In 1973, Bergman et al [51] defined more closely the scope and limitation of the reaction of N-(α-haloacyl)pyridinium salts with indole in order to briefly study the possibility of using 3-(2-haloacyl)indoles as synthetic building blocks. So, the reactions were carried out by slow addition of the α-haloacyl halide to pyridine and indole in toluene or in some cases in dioxan [52] . The desired 3-isomer (1b,7b,c) was often accompanied by the 1-isomer (10a-c) (Scheme 5).…”

Section: Acylation Of Indole Using N-(α-haloacyl)pyridinium Saltsmentioning

confidence: 99%

Chemistry of 3-(2-Haloacyl)indoles

El‐Mekabaty

2015

Synthetic Communications

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“…A recently described class of anti-prion compound is indole-3-glyoxylamide [107][108][109]. Derivatives of these compounds are actually in clinical trials for a variety of other medical conditions, including acute coronary syndrome [110,111], HIV infection [112], and some cancers [113].…”

Section: Indole-3-glyoxylamidesmentioning

confidence: 99%

Prion Disease: Chemotherapeutic Strategies

Sim

2012

IDDT

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Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with antiprion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemicalbased treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.

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Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

Cited by 25 publications

References 40 publications

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy

Chemistry of 3-(2-Haloacyl)indoles

Prion Disease: Chemotherapeutic Strategies

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