Azaphilones from an Endophytic Penicillium sp. Prevent Neuronal Cell Death via Inhibition of MAPKs and Reduction of Bax/Bcl-2 Ratio
| Autor: | Ki Sung Kang, Stephen T. Deyrup, Sang Hee Shim, Jae-Kyeong Kim, Ji Yun Baek, Hyukjae Choi, Sunghee Bang, SungJin Kim, Geum Jin Kim |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Programmed cell death Chemistry Organic Chemistry Cell Glutamate receptor Neurotoxicity Pharmaceutical Science medicine.disease Neuroprotection Analytical Chemistry medicine.anatomical_structure Complementary and alternative medicine Apoptosis Drug Discovery medicine Molecular Medicine Phosphorylation Intracellular |
| Zdroj: | Journal of Natural Products. 84:2226-2237 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.1c00298 |
| Popis: | Fourteen azaphilone-type polyketides (1-14), including nine new ones (1-6 and 8-10), were isolated from cultures of Vitex rotundifolia-associated Penicillium sp. JVF17, and their structures were determined by spectroscopic analysis together with computational methods and chemical reactions. Neuroprotective effects of the isolated compounds were evaluated against glutamate-induced neurotoxicity. Treatment with compounds 3, 6, 7, and 11-14 increased cell viabilities of hippocampal neuronal cells damaged by glutamate, with compound 12 being the most potent. Compound 12 markedly decreased intracellular Ca2+ and nuclear condensation levels. Mechanistically, molecular markers of apoptosis induced by treatment with glutamate, i.e., phosphorylation of MAPKs and elevated Bax/Bcl-2 expression ratio, were significantly lowered by compound 12. The azaphilones with an isoquinoline core structure were more active than those with pyranoquinones, but N-substitution decreased the activity. This study, including the structure-activity relationship, indicates that the azaphilone scaffold is a promising lead toward the development of novel neuroprotective agents. |
| Databáze: | OpenAIRE |
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