Cytotoxic Activity of Germacrane-Type Sesquiterpene Lactones from Dimerostemma aspilioides
| Autor: | Jerónimo Laiolo, Sara M. Palacios, Mariana Belén Joray, María Cecilia Carpinella, María F García Manzano |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
Germacranolide Cell cycle checkpoint 010405 organic chemistry Chemistry Organic Chemistry Pharmaceutical Science medicine.disease 01 natural sciences Peripheral blood mononuclear cell 0104 chemical sciences Analytical Chemistry Multiple drug resistance 010404 medicinal & biomolecular chemistry Leukemia Complementary and alternative medicine Biochemistry Drug Discovery medicine Molecular Medicine Cytotoxic T cell Cytotoxicity K562 cells |
| Zdroj: | Journal of Natural Products. 83:1909-1918 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.0c00115 |
| Popis: | The need for effective candidates as cytotoxic drugs that at the same time challenge cancer multidrug resistance encouraged a search for these in plants of central Argentina. Bioassay-guided fractionation of the cytotoxic extract from Dimerostemma aspilioides led to the isolation of the germacranolide tomenphantin A (1), along with three new analogues (2-4). These efficiently inhibited the proliferation of the leukemia cell lines K562 and CCRF-CEM and their resistant variants, Lucena 1 and CEM/ADR5000, respectively, with IC50 values ranging from 0.40 to 7.7 μM. The structures and relative configurations of compounds 1-4 were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound 1 (IC50 = 0.40-5.1 μM), and, therefore, this was selected as a model for a mechanistic study, which revealed that its antiproliferative effect was mediated by cell cycle arrest in the G2/M phase followed by apoptosis. The activity of compound 1 was selective, given the absence of cytotoxicity toward peripheral blood mononuclear cells. The results show the potential of these compounds, and in particular of compound 1, as leads for the development of drug candidates to fight sensitive and resistant leukemia cells. |
| Databáze: | OpenAIRE |
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