EVALUATION OF AMINOINDOLE CARBOXAMIDES AND TRIAZINES AS POTENTIAL ANTI-AGGREGATION AGENTS OF PROTEIN MISFOLDING DISEASES
Eduardo Ramirez
;
Purdue University Graduate School,2024.
DOI:
10.25394/PGS.25685910.v1
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Abstract: Alzheimer’s (AD) and Parkinson’s (PD) are the most common debilitating disorders to affect the geriatric population. There are two pathological hallmarks which correlate with the manifestation of AD: the first is the formation amyloid-β plaques (Aβ plaques) in the extracellular space and the second is the aggregation of hyperphosphorylated tau protein (p-tau) which develops into neurofibrillary tangles (NFTs) in the interneuron. PD results from the misfolding of α-synuclein (α-syn) which then aggregates to form Lewy bodies. In over 50% of AD cases aggregated α-syn_x005f_x0002_containing Lewy bodies are presently displayed. My research projects focus on the dual targeting of small molecules to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to reduce the spread of AD and related dementias. Not very many drug discovery programs focus on the specific isoforms of the tau protein. We set out to establish two series of aminoindole compounds connected by a carboxamide or triazine linker to evaluate the effectiveness of both families in decreasing the amount of misfolded α-syn and tau protein. Biophysical methods such as thioflavin T (ThT) fluorescence assays, photoinduced cross-linking of unmodified proteins (PICUP), and transmission electron microscopy (TEM) were deployed to assess the anti_x005f_x0002_aggregation potential of our aminoindole derivatives. M17D intracellular inclusion assay was used to detect the potency of our best compounds in reducing α-syn inclusions. We found that compounds A2, A8, and A17 from the amide series and compound T10 from the triazine series were effective in reducing the formation of α-syn and tau isoform 2N4R fibrils and oligomers in a dose-dependent manner. This was observed through the use of ThT fluorescence and PICUP assays and was validated with TEM. These same compounds reduced the development of α-syn inclusions in M17D neuroblastoma cells. Compounds A8 of the amide project and T10 of the triazine series were the most effective in preventing α-syn and tau isoform 2N4R aggregation. Compound T10 also showed reduction of ex vivo Aβ plaques and paired helical filaments (PHFs) in the brain tissue of a deceased AD patient showcasing its translational potential. These results demonstrate the potential of 4-aminoindole derivatives in preventing the aggregation α-syn and tau (2N4R isoform) proteins. The triazine derivatives series demonstrates the effectiveness of N_x005f_x0002_linked triazines in reducing misfolding of α-syn and tau in contrast to O-linked triazines and display the importance of symmetry in drug design.
Keywords:
Alzheimer's disease ;
Amide ;
alpha-synuclein (synuclein alpha) ;
fibril oligomer ;
tau isoform 2n4r ;
anti-aggregation compounds ;
hyperphosphorylated protein tau ;
paired helical filaments ;
drug discovery ;
triazine compound
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Systematic analysis of gut bacterial carcinogen metabolism and its functional consequences
Boyao Zhang
;
George-Eugen Maftei
;
Bartosz Bartmanski
, et al.
bioRxiv,2024:2024.05.20.595058.
DOI:
10.1101/2024.05.20.595058
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Abstract: Organic carcinogens, in particular DNA-reactive compounds, contribute to the irreversible initiation step of tumorigenesis through introduction of genomic instability. Although carcinogen bioactivation and detoxification by human enzymes has been extensively studied, carcinogen biotransformation by human-associated bacteria, the microbiota, has not yet been systematically investigated. We tested the biotransformation of 68 mutagenic carcinogens by 34 bacterial species representative for the upper and lower human gastrointestinal tract and found that the majority (41) of the tested carcinogens undergo bacterial biotransformation. To assess the functional consequences of microbial carcinogen metabolism, we developed a pipeline to couple gut bacterial carcinogen biotransformation assays with Ames mutagenicity testing and liver biotransformation experiments. This revealed a bidirectional crosstalk between gut microbiota and host carcinogen metabolism, which we validated in gnotobiotic mouse models. Overall, the systematic assessment of gut microbiota carcinogen biotransformation and its interplay with host metabolism highlights the gut microbiome as an important modulator of exposome-induced tumorigenesis.
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Discovery of 4-aminoindole carboxamide derivatives to curtail alpha-synuclein and tau isoform 2N4R oligomer formation
Ramirez, Eduardo
;
Min, Sehong
;
Ganegamage, Susantha K.
, et al.
Results Chem.,2023,5,100938.
DOI:
10.1016/j.rechem.2023.100938
PubMed ID:
37346091
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Abstract: Alzheimer's disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular beta-amyloid (Abeta) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using alpha-synuclein (alpha-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophys. methods, such as thioflavin T fluorescence assays, photo-induced crosslinking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming alpha-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on alpha-syn and the 2N4R isoform of tau. At a concentration of 40 μM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone alphaSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of alpha-syn and tau (2N4R isoform) for further optimization prior to pre-clin. studies.
Keywords:
Alzheimer's disease ;
Amide ;
Alpha-synuclein ;
Fibril ;
Oligomer
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