ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. ...Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-ҡBs. We previously reported that SRI-22819 increases NF-ҡB expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.
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•Development of novel compounds for the treatment of amyotrophic lateral sclerosis.•Abnormality of Superoxide dismutase 1 function causes hyper-generation of reactive oxygen species.•Superoxide dismutase 2 works in conjunction with Superoxide dismutase 1 to detoxify reactive oxygen species.•Structure-activity relationship studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.•Hybrid compounds based on N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine and Ataluren.
Soluble oligomeric amyloid-β (Aβ) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active ...compounds was robotically screened for inhibitors of Aβ oligomer formation with a single-site biotinylated Aβ(1–42) oligomer assembly assay. Several quinoline-like compounds were identified with IC
50's <10
μM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Aβ oligomer formation up to a concentration of 100
μM. Analogs of clioquinol have shown activity in reducing Aβ levels and improving behavioral deficits in mouse models of Aβ pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation
in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Aβ oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.
Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested ...that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an Emax ≥70% of 5 µM hemin and EC50 <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.
Abstract Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many ...past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.
In particular, SRI36160 greatly inhibits the activity of firefly luciferase in the ATP-dependent luciferase ATPlite assay (Perkin Elmer) for cell proliferation studies, although SRI36160 has little ...or no effect on the activity of firefly luciferase in the CellTiter-Glo assay (Promega) for cell proliferation studies....as the Super8XTOPFlash luciferase Wnt reporter assay is also based on firefly luciferase activity, the data and Wnt activity IC50 values described in Fig. 1A, 1B, 2A, 3A & 3B are likely to be inaccurate.
Polyphenolic compounds including a number of natural products such as resveratrol, curcumin, catechin derivatives, and nordihydroguaiaretic acid have effects on the assembly of Aβ fibrils and ...oligomers as well as on fibril morphology. Based on a lead structure obtained from a screen of a small molecule diversity library, simple benzoic acid derivatives distinguished by the number and position of hydroxyls on the aromatic ring displayed different abilities to dissociate preformed biotinyl-Aβ(1–42) oligomers. The 2,3-, 2,5-, and 3,4-dihydroxybenzoic acid (DHBA) isomers were active oligomer dissociators. The remaining DHBA isomers and the monohydroxy and unsubstituted benzoic acids were inactive and did not compete with the active compounds to block oligomer dissociation. None of the compounds blocked oligomer assembly, indicating that they do not interact with monomeric Aβ to shift the oligomer–monomer equilibrium. Dissociating activity was not associated with quinone redox cycling capacity of the compounds. Gallic acid (3,4,5-trihydroxybenzoic acid) stabilized biotinyl-Aβ(1–42) oligomers against intrinsic dissociation and blocked the effects of the active dissociators, independent of the concentration of dissociator. A model for the mechanism of action of the DHBA dissociators proposes that these compounds destabilize oligomer structure promoting progressive monomer dissociation rather than fissioning oligomers into smaller, but still macromolecular, species. Gallic acid blocks dissociation by stabilizing oligomers against this process.
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One therapeutic approach for Alzheimer’s disease is to inhibit the cleavage of the amyloid precursor protein (APP) by γ-secretase. At the beginning of a series of studies from our ...laboratories, a series of novel γ-amino alcohols (1) were found to possess γ-secretase inhibitory activity and Notch-sparing effects. A new one-pot synthesis of γ-amino alcohols and the structure–activity relationship (SAR) of these analogs will be discussed.
Several gamma-secretase inhibitors (GSI) are in clinical trials for the treatment of Alzheimer's disease (AD). This enzyme mediates the proteolytic cleavage of amyloid precursor protein (APP) to ...generate amyloid beta protein, Abeta, the pathogenic protein in AD. The gamma-secretase also cleaves Notch to generate Notch Intracellular domain (NICD), the signaling molecule that is implicated in tumorigenesis.
We have developed a method to examine live zebrafish that were each treated with gamma-secretase inhibitors (GSI), DAPT {N- N-(3,5-Difluorophenacetyl-L-alanyl)-S-phenylglycine t-Butyl Ester}, Gleevec, or fragments of Gleevec. These compounds were first tested in a cell-based assay and the effective concentrations of these compounds that blocked Abeta generation were quantitated. The mortality of zebrafish, as a result of exposure to different doses of compound, was assessed, and any apoptotic processes were examined by TUNEL staining. We then used conventional and automatic microscopes to acquire images of zebrafish and applied algorithms to automate image composition and processing. Zebrafish were treated in 96- or 384-well plates, and the phenotypes were analyzed at 2, 3 and 5 days post fertilization (dpf). We identified that AD95, a fragment of Gleevec, effectively blocks Abeta production and causes specific phenotypes that were different from those treated with DAPT. Finally, we validated the specificity of two Notch phenotypes (pigmentation and the curvature of tail/trunk) induced by DAPT in a dose-dependent manner. These phenotypes were examined in embryos treated with GSIs or AD95 at increasing concentrations. The expression levels of Notch target gene her6 were also measured by in situ hybridization and the co-relationship between the levels of Notch inhibition by DAPT and AD95 and the severity of phenotypes were determined.
The results reported here of the effects on zebrafish suggest that this newly developed method may be used to screen novel GSIs and other leads for a variety of therapeutic indications.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the ...request of the Authors. Following publication of this paper in Cancer Letters, the authors identified that SRI36160 and its analogs are potential inhibitors of the firefly luciferase. In particular, SRI36160 greatly inhibits the activity of firefly luciferase in the ATP-dependent luciferase ATPlite assay (Perkin Elmer) for cell proliferation studies, although SRI36160 has little or no effect on the activity of firefly luciferase in the CellTiter-Glo assay (Promega) for cell proliferation studies. This suggests that the activity of firefly luciferase can be significantly inhibited by SRI36160 in certain assay systems. As the cell proliferation data described in Fig. 5 in this paper was obtained from the ATP-dependent luciferase ATPlite assay, the data and cell proliferation IC50 values are incorrect. In addition, as the Super8XTOPFlash luciferase Wnt reporter assay is also based on firefly luciferase activity, the data and Wnt activity IC50 values described in Fig. 1A, 1B, 2A, 3A & 3B are likely to be inaccurate. All other data in this paper are correct. However in order to ensure the highest standard of data accuracy all the authors of this paper have requested that it be retracted from Cancer Letters.
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