Synthesis of 9-substituted 2,3,4,9-tetrahydro-1H-carbazole derivatives and evaluation of their anti-prion activity in TSE-infected cells

Kimura, Tsutomu; Hosokawa-Muto, Junji; Asami, Kōji; Murai, Toshiaki; Kuwata, Kazuo

doi:10.1016/j.ejmech.2011.08.039

Cited by 34 publications

(26 citation statements)

References 22 publications

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“…494 A structure-activity relationship study of the pyrazole derivative of carbazole led to the understanding that a tricyclic aromatic ring with hydroxyl and amino groups inhibited PrP Sc fibrillization in PrP Sc -infected neuronal cells. 492 …”

Section: Prions and Prion Diseasesmentioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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Section: Prions and Prion Diseasesmentioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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“…However, the continuous administration of quinacrine led to liver dysfunction, and the treatment had to be discontinued (Nakajima et al, 2004). As a continuation of our rational antiprion drug discovery and development studies (Hosokawa-Muto et al, 2009;Ishikawa et al, 2009;Kimura et al, 2011a;Kimura et al, 2011b;Kuwata et al, 2007;Yamamoto and Kuwata, 2009), we found that the administration of GN8 derivative 1 prolonged the survival time of TSE-infected mice and slowed the development of neurological and psychological symptoms in TSE-infected macaques (Yamaguchi et al, 2019). Since 1 is a promising candidate for antiprion agent development, it is of great importance to identify its toxicological features from the standpoint of the practical use of compound 1.…”

Section: Discussionmentioning

confidence: 99%

Oral toxicity study of an antiprion compound N,N’-[(cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] in rats and cynomolgus monkeys

Hosokawa-Muto

Kimura

Kuwata

2019

Fundam. Toxicol. Sci.

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-N,N'-[(Cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] (1) is a novel antiprion compound, termed a designer molecular chaperone, that we recently developed. The administration of compound 1 prolonged the survival time of prion-infected mice and slowed the development of neurological and psychological symptoms in prion-infected macaques. The aim of this study was to investigate the oral toxicity of compound 1 to rats and cynomolgus monkeys. Compound 1 was administered orally to rats at doses of 31.3, 125, and 500 mg/kg. Although two of ten rats died at a dose of 500 mg/kg, no serious safety problems were identified at doses of 31.3 and 125 mg/kg. Repeated oral administration of compound 1 to rats at a dosage of 31.3 mg/kg/day for a week led to no significant toxic effects in the rats. An acute toxicity test in cynomolgus monkeys revealed that the administration of compound 1 at a dose of 60 mg/kg induced vomiting and fecal abnormalities. The monkeys did not die even at a dose of 250 mg/kg. A dose-dependent increase in the plasma concentrations of compound 1 in the cynomolgus monkeys as measured by LC/MS/MS analysis indicated that compound 1 migrated into the bloodstream. These results suggest that compound 1 might have potential as a therapeutic agent for prion diseases.

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“…Compounds 103 and 104 ( Figure 21 ) are clearly distinct in terms of their chemical structure; yet, it is interesting to note the presence of key common elements in both structures: the number of hydrogen bond donors and acceptors, a nitrogen-containing five-membered ring, aromatic rings—one of which substituted with a fluorine atom, as well as a free hydroxy group. Compound 103 was also identified as a promising anti-prion scaffold by Kimura and co-workers in 2011 [ 98 ].…”

Section: Synthesis and Mode Of Action Of Glyco-based And Aromatic mentioning

confidence: 99%

“…Compound 104 was developed inspired on compound 103 ( Figure 21 ), previously reported for its affinity towards PrP C while displaying an IC 50 of 8.54 μM against PrP res accumulation in GT1-7 cells infected with Fukoka 1 (FK-1) [ 98 ]. It was synthesized together with a library of fortyseven dihydrocarbazole analogs and derivatives, which were subsequently tested to allow a comprehensive structure-activity relationship study on the activity of the lead compound.…”

Section: Synthesis and Mode Of Action Of Glyco-based And Aromatic mentioning

confidence: 99%

Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life

2017

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Prion diseases are fatal neurodegenerative disorders caused by protein misfolding and aggregation, affecting the brain progressively and consequently the quality of life. Alzheimer’s is also a protein misfolding disease, causing dementia in over 40 million people worldwide. There are no therapeutics able to cure these diseases. Cellular prion protein is a high-affinity binding partner of amyloid β (Aβ) oligomers, the most toxic species in Alzheimer’s pathology. These findings motivate the development of new chemicals for a better understanding of the events involved. Disease control is far from being reached by the presently known therapeutics. In this review we describe the synthesis and mode of action of molecular entities with intervention in prion diseases’ biological processes and, if known, their role in Alzheimer’s. A diversity of structures is covered, based on glycans, steroids and terpenes, heterocycles, polyphenols, most of them embodying aromatics and a structural complexity. These molecules may be regarded as chemical tools to foster the understanding of the complex mechanisms involved, and to encourage the scientific community towards further developments for the cure of these devastating diseases.

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Synthesis of 9-substituted 2,3,4,9-tetrahydro-1H-carbazole derivatives and evaluation of their anti-prion activity in TSE-infected cells

Cited by 34 publications

References 22 publications

Implications of peptide assemblies in amyloid diseases

Implications of peptide assemblies in amyloid diseases

Oral toxicity study of an antiprion compound <i>N</i>,<i>N</i><i>’</i>-[(cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] in rats and cynomolgus monkeys

Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life

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