RESUMO
Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads.
Assuntos
Produtos Biológicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Fatores de Crescimento Neural/síntese química , Fatores de Crescimento Neural/farmacologia , Terpenos/química , Materiais Biomiméticos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fatores de Crescimento Neural/química , EstereoisomerismoRESUMO
Glioblastoma multiforme (GBM) is a lethal grade IV glioma (WHO classification) and widely prevalent primary brain tumor in adults. GBM tumors harbor cellular heterogeneity with the presence of a small subpopulation of tumor cells, described as GBM cancer stem cells (CSCs) that pose resistance to standard anticancer regimens and eventually mediate aggressive relapse or intractable progressive GBM. Existing conventional anticancer therapies for GBM do not target GBM stem cells and are mostly palliative; therefore, exploration of new strategies to target stem cells of GBM has to be prioritized for the development of effective GBM therapy. Recent developments in the understanding of GBM pathophysiology demonstrated dysregulation of epigenetic mechanisms along with the genetic changes in GBM CSCs. Altered expression/activity of key epigenetic regulators, especially histone deacetylases (HDACs) in GBM stem cells has been associated with poor prognosis; inhibiting the activity of HDACs using histone deacetylase inhibitors (HDACi) has been promising as mono-therapeutic in targeting GBM and in sensitizing GBM stem cells to an existing anticancer regimen. Here, we review the development of pan/selective HDACi as potential anticancer agents in targeting the stem cells of glioblastoma as a mono or combination therapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Epigênese Genética , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologiaRESUMO
Small-molecule inhibitors of HDACs (HDACi) induce hyperacetylation of histone and nonhistone proteins and have emerged as potential therapeutic agents in most animal models tested. The established HDACi vorinostat and tubastatin-A alleviate neurodegenerative and behavioral conditions in animal models of neuropsychiatric disorders restoring the neurotrophic milieu. In spite of the neuroactive pharmacological role of HDACi (vorinostat and tubastatin-A), they are limited by efficacy and toxicity. Considering these limitations and concern, we have designed novel compounds 3-11 as potential HDACi based on the strategic crafting of the key pharmacophoric elements of vorinostat and tubastatin-A into architecting a single molecule. The molecules 3-11 were synthesized through a multistep reaction sequence starting from carbazole and were fully characterized by NMR and mass spectral analysis. The novel molecules 3-11 showed remarkable pan HDAC inhibition and the potential to increase the levels of acetyl H3 and acetyl tubulin. In addition, few novel HDAC inhibitors 4-8, 10, and 11 exhibited significant neurite outgrowth-promoting activity with no observable cytotoxic effects, and interestingly, compound 5 has shown comparably more neurite growth than the parent compounds vorinostat and tubastatin-A. Also, compound 5 was evaluated for possible mood-elevating effects in a chronic unpredictable stress model of Zebrafish. It showed potent anxiolytic and antidepressant-like effects in the novel tank test and social interaction test, respectively. Furthermore, the potent in vitro and in vivo neuroactive compound 5 has shown selectivity for class II over class I HDACs. Our results suggest that the novel carbazole-based HDAC inhibitors, crafted with vorinostat and tubastatin-A pharmacophoric moieties, have potent neurite outgrowth activity and potential to be developed as therapeutics to treat depression and related psychiatric disorders.
RESUMO
Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A-D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A-D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders.
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BACKGROUND: Natural products from lichens are widely investigated for their biological properties, yet their potential as central nervous system (CNS) therapeutic agents is less explored. PURPOSE: The present study investigated the neuroactive properties of selected lichen compounds (atranorin, perlatolic acid, physodic acid and usnic acid), for their neurotrophic, neurogenic and acetylcholine esterase (AChE) activities. METHODS: Neurotrophic activity (neurite outgrowth) was determined using murine neuroblastoma Neuro2A cells. A MTT assay was performed to assess the cytotoxicity of compounds at optimum neurotrophic activity. Neuro2A cells treated with neurotrophic lichen compounds were used for RT-PCR to evaluate the induction of genes that code for the neurotrophic markers BDNF and NGF. Immunoblotting was used to assess acetyl H3 and H4 levels, the epigenetic markers associated with neurotrophic and/or neurogenic activity. The neurogenic property of the compounds was determined using murine hippocampal primary cultures. AChE inhibition activity was performed using a modified Ellman's esterase method. RESULTS: Lichen compounds atranorin, perlatolic acid, physodic acid and (+)-usnic acid showed neurotrophic activity in a preliminary cell-based screening based on Neuro2A neurite outgrowth. Except for usnic acid, no cytotoxic effects were observed for the two depsides (atranorin and perlatolic acid) and the alkyl depsidone (physodic acid). Perlatolic acid appears to be promising, as it also exhibited AChE inhibition activity and potent proneurogenic activity. The neurotrophic lichen compounds (atranorin, perlatolic acid, physodic acid) modulated the gene expression of BDNF and NGF. In addition, perlatolic acid showed increased protein levels of acetyl H3 and H4 in Neuro2A cells. CONCLUSION: These lichen depsides and depsidones showed neuroactive properties in vitro (Neuro2A cells) and ex vivo (primary neural stem or progenitor cells), suggesting their potential to treat CNS disorders.
Assuntos
Benzoatos/farmacologia , Benzofuranos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Depsídeos/farmacologia , Dibenzoxepinas/farmacologia , Hidroxibenzoatos/farmacologia , Lactonas/farmacologia , Líquens/química , Acetilcolinesterase/metabolismo , Animais , Benzoatos/uso terapêutico , Benzofuranos/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular , Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Inibidores da Colinesterase/farmacologia , Depsídeos/uso terapêutico , Dibenzoxepinas/uso terapêutico , Expressão Gênica , Hidroxibenzoatos/uso terapêutico , Lactonas/uso terapêutico , Camundongos , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Células-Tronco Neurais , Neurogênese/efeitos dos fármacos , Neurogênese/genéticaRESUMO
In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.