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Boron-based hybrids as novel scaffolds for the development of drugs with neuroprotective properties.

ABSTRACT: Novel boron-based compounds (BBCs) were synthesized and evaluated as potential candidates for the development of novel drugs against Alzheimer's disease (AD). The neuroprotective profile of novel BBCs was evaluated using Aβ1-42-treated-SH-SY5Y cells while their antioxidant activity was evaluated by total antioxidant capacity (TAC) and total oxidative status (TOS) assays. Results showed that BLA (a novel boron-based hybrid containing an antioxidant portion) inhibited cell death induced by Aβ1-42-exposure in differentiated SH-SY5Y cells, resulting in an increase in cell viability by 25-33% (MTT assay) and by 63-71% (LDH assay) in a concentration range of 25-100 μM. Antioxidant assays demonstrated a good capability of BLA to counteract the oxidative status. Moreover, BLA possessed a significant ability to inhibit acetylcholinesterase (AChE) (22.96% at 50 μM), an enzyme whose enzymatic activity is increased in AD patients. In the present work, absorption and distribution properties of boron-based hybrids were predicted using Pre-ADMET software. In vitro preliminary results suggested that boron-based hybrids could be new structural scaffolds for the development of novel drugs for the management of AD.

SUBMITTER: Cacciatore I

PROVIDER: S-EPMC8597428 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Boron-based hybrids as novel scaffolds for the development of drugs with neuroprotective properties.

Cacciatore Ivana I Turkez Hasan H Di Rienzo Annalisa A Ciulla Michele M Mardinoglu Adil A Di Stefano Antonio A

RSC medicinal chemistry 20210813 11

Novel boron-based compounds (BBCs) were synthesized and evaluated as potential candidates for the development of novel drugs against Alzheimer's disease (AD). The neuroprotective profile of novel BBCs was evaluated using Aβ1-42-treated-SH-SY5Y cells while their antioxidant activity was evaluated by total antioxidant capacity (TAC) and total oxidative status (TOS) assays. Results showed that <b>BLA</b> (a novel boron-based hybrid containing an antioxidant portion) inhibited cell death induced by ...[more]

PMID: 34825189

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Project description:Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β-induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.

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Boron-based hybrids as novel scaffolds for the development of drugs with neuroprotective properties.

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Boron-based hybrids as novel scaffolds for the development of drugs with neuroprotective properties.

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