RESUMO
We present the preparation of a series of novel natural product-like homobarrelenones, norcaranes, and dihydrofluorenones through a diversity-oriented synthetic (DOS) strategy that combines Diels-Alder reactions and phototransformations, as well as their biological evaluation against MCF-7, HT-29, and NCI-H460 human tumor cells. Six of these demonstrated activities in the micromolar range against the three cell lines, and none were predicted as cytotoxic against human nontumor cells according to in silico studies. In addition, within the set of active derivatives, three exhibited low unspecific cytotoxicity in a sperm motility assay. The rich functionality of the new compounds makes them ideal candidates for exhaustive structure-activity relationship studies.
Assuntos
Antineoplásicos , Biflavonoides , Masculino , Humanos , Relação Estrutura-Atividade , Tropolona/farmacologia , Motilidade dos Espermatozoides , Biflavonoides/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Estrutura Molecular , Proliferação de CélulasRESUMO
Phytochelators have been studied as templates for designing new drugs for chelation therapy. This work evaluated key chemical and biological properties of five candidate phytochelators for iron overload diseases: maltol, mimosine, morin, tropolone, and esculetin. Intra- and extracellular iron affinity and antioxidant activity, as well as the ability to scavenge iron from holo-transferrin, were studied in physiologically relevant settings. Tropolone and mimosine (and, to a lesser extent, maltol) presented good binding capacity for iron, removing it from calcein, a high-affinity fluorescent probe. Tropolone and mimosine arrested iron-mediated oxidation of ascorbate with the same efficiency as the standard iron chelator DFO. Also, both were cell permeant and able to access labile pools of iron in HeLa and HepG2 cells. Mimosine was an effective antioxidant in cells stressed by iron and peroxide, being as efficient as the cell-permeant iron chelator deferiprone. These results reinforce the potential of those molecules, especially mimosine, as adjuvants in treatments for iron overload.
Assuntos
Quelantes de Ferro , Sobrecarga de Ferro , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Desferroxamina , Humanos , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Mimosina/uso terapêutico , Piridonas/uso terapêutico , Tropolona/uso terapêuticoRESUMO
Pseudomonas donghuensis strain SVBP6, an isolate from an agricultural plot in Argentina, displays a broad-spectrum and diffusible antifungal activity, which requires a functional gacS gene but could not be ascribed yet to known secondary metabolites typical of Pseudomonas biocontrol species. Here, we report that Tn5 mutagenesis allowed the identification of a gene cluster involved in both the fungal antagonism and the production of a soluble tropolonoid compound. The ethyl acetate extract from culture supernatant showed a dose-dependent inhibitory effect against the phytopathogenic fungus Macrophomina phaseolina. The main compound present in the organic extract was identified by spectroscopic and X-ray analyses as 7-hydroxytropolone (7HT). Its structure and tautomerism was confirmed by preparing the two key derivatives 2,3-dimethoxy- and 2,7-dimethoxy-tropone. 7HT, but not 2,3- or 2,7-dimethoxy-tropone, mimicked the fungal inhibitory activity of the ethyl acetate extract from culture supernatant. The activity of 7HT, as well as its production, was barely affected by the presence of up to 50 µM added iron (Fe+2 ). To summarize, P. donghuensis SVBP6 produces 7HT under the positive control of the Gac-Rsm cascade and is the main active metabolite responsible for the broad-spectrum inhibition of different phytopathogenic fungi.
Assuntos
Antibiose/genética , Antifúngicos/metabolismo , Ascomicetos/crescimento & desenvolvimento , Pseudomonas/metabolismo , Tropolona/análogos & derivados , Antibiose/fisiologia , Argentina , Proteínas de Bactérias/genética , Mutagênese/efeitos dos fármacos , Pseudomonas/genética , Fatores de Transcrição/genética , Transposases/genética , Tropolona/metabolismoRESUMO
The goal of this work was to display the anticancer and antimetastatic activity of a copper(II) with tropolone (trp), complex [Cu(trp)2] toward human breast cancer cells in monolayer (2D) and spheroids (3D). Cytotoxicity assays against MCF7 (IC50(complex) = 5.2 ± 1.8 µM, IC50(CDDP) = 19.3 ± 2.1 µM) and MDA-MB-231 (IC50(complex) = 4.0 ± 0.2 µM, IC50(CDDP) = 27.0 ± 1.9 µM) demonstrate that [Cu(trp)2] exert greater antitumor potency than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Besides, [Cu(trp)2] inhibits cell migration by reducing the metalloproteinases activities and the compound undergoes the breast cancer cells to apoptosis at lower concentrations (2.5-10 µM). Moreover, [Cu(trp)2] overcame CDDP presenting an IC50 value 26-fold more lower against breast multicellular spheroids ((IC50(complex) = 4.9 µM, IC50(CDDP) = 130 µM)). Also, our results showed that [Cu(trp)2] inhibited the cell migration and cell invasion of breast multicellular spheroids, showing that [Cu(trp)2] exhibited antimetastatic properties. On the other hand, [Cu(trp)2] reduced mammosphere forming capacity affecting the size and number of mammospheres. Taken together, [Cu(trp)2] exhibited anticancer and antimetastatic properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/química , Tropolona/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Complexos de Coordenação/química , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica , Esferoides Celulares/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Two new sesquiterpenoid tropolone glycosides, liriosmasides A (1) and B (2), along with two known compounds, secoxyloganin and oplopanpheside C, were isolated from a methanol extract of the roots of Liriosma ovata. The structures of 1 and 2 were elucidated by spectroscopic methods including 1D and 2D NMR and by high-resolution mass spectrometry involving an ultra-high-performance liquid chromatography-quadrupole-orbital ion trap mass spectrometric (UHPLC-Q-Orbitrap MS) method. Compound 1 showed weak inhibitory activity against HIV RNase H.