| 1. |
- Kabakci, Zeynep, et al.
(författare)
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Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.
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| 2. |
- Semwal, Prabhakar, et al.
(författare)
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The medicinal chemistry of Urtica dioica L.: from preliminary evidence to clinical studies supporting its neuroprotective activity
- 2023
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Ingår i: NATURAL PRODUCTS AND BIOPROSPECTING. - : SPRINGERNATURE. - 2192-2195. ; 13:1
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Forskningsöversikt (refereegranskat)abstract
- Urtica dioica is a perennial herb from the family of Urticaceae that is commonly known as stinging nettle. This plant is widespread in Europe, Africa, America, and a part of Asia, as it adapts to different environments and climatic conditions. The leaves, stalk, and bark of U. dioica found applications in the field of nutrition, cosmetics, textile, pest control and pharmacology. In this connection, bioactive chemical constituents such as flavonoids, phenolic acids, amino acids, carotenoids, and fatty acids have been isolated from the plant. With this review, we aim at providing an updated and comprehensive overview of the contributions in literature reporting computational, in vitro, pre-clinical and clinical data supporting the therapeutic applications of U. dioica. Experimental evidence shows that U. dioica constituents and extracts can provide neuroprotective effects by acting through a combination of different molecular mechanisms, that are discussed in the review. These findings could lay the basis for the identification and design of more effective tools against neurodegenerative diseases.
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