RESUMEN
Chalcones are a group of molecules with recognized biological potential against many diseases, including cancer. Thus, studies on this structure and derivatives have become an attractive chemical strategy to optimize their observed biological activities. One of the synthetic routes used to obtain chalcone derivatives is esterification using either commercial acid chlorides or carboxylic acids. This work focuses on preparing chalcone derivatives and investigating their biological potential against cancer cells. Compound 3'-hydroxychalcone (1) was synthetized by Claisen-Schmidt condensation followed by esterification of the 3'-OH, resulting in eight compounds named 1a-b and 2a-f. All structures were confirmed by 1H and 13C NMR and FT-IR, and cytotoxicity was evaluated in the HCT 116 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma), and CCD-18Co (nontumoral colon fibroblasts) cell lines. Chalcone derivatives were generally more active toward the colon cancer cell line, and 1a and 2b were selected for IC50 determination, presenting IC50 values of approximately 10â µM in HCT 116 cells and above 20â µM in both MCF7 and CDC-18-Co cells, suggesting moderate selectivity. Additionally, we tested compounds 1a and 2b in combination with doxorubicin, but they did not act synergistically with this anthracycline. In conclusion, considering these compounds obtained by the esterification reaction, 1a and 2d showed better results against cytotoxic cells.
RESUMEN
Bacillus subtilis species complex is known as lipopeptide-producer with biotechnological potential for pharmaceutical developments. This study aimed to identify lipopeptides from a bacterial isolate and evaluate their antifungal effects. Here, we isolated and identified a lipopeptide-producing bacterium as a species of Bacillus subtilis complex (strain UL-1). Twenty lipopeptides (six iturins, six fengycins, and eight surfactins) were identified in the crude extract (CE) and fractions (F1, F2, F3, and F4), and the highest content of total lipopeptides was observed in CE and F2. The chemical quantification data corroborate with the hemolytic and antifungal activities that CE and F2 were the most hemolytic and inhibited the fungal growth at lower concentrations against Fusarium spp. In addition, they caused morphological changes such as shortening and/or atypical branching of hyphae and induction of chlamydospore-like structure formation, especially in Fusarium solani. CE was the most effective in inhibiting the biofilm formation and in disrupting the mature biofilm of F. solani reducing the total biomass and the metabolic activity at concentrations ≥ 2 µg/mL. Moreover, CE significantly inhibited the adherence of F. solani conidia on contact lenses and nails as well as disrupted the pre-formed biofilms on nails. CE at 100 mg/kg was nontoxic on Galleria mellonella larvae, and it reduced the fungal burden in larvae previously infected by F. solani. Taken together, the lipopeptides obtained from strain UL-1 demonstrated a potent anti-Fusarium effect inducing morphological alterations and antibiofilm activities. Our data open further studies for the biotechnological application of these lipopeptides as potential antifungal agents. KEY POINTS: ⢠Lipopeptides inhibit Fusarium growth and induce chlamydospore-like structures. ⢠Lipopeptides hamper the adherence of conidia and biofilms of Fusarium solani. ⢠Iturins, fengycins, and surfactins were associated with antifungal effects.
Asunto(s)
Antifúngicos , Bacillus subtilis , Bacillus subtilis/metabolismo , Antifúngicos/química , Esporas Fúngicas/metabolismo , Biopelículas , Lipopéptidos/metabolismo , Péptidos Cíclicos/metabolismo , Enfermedades de las Plantas/microbiologíaRESUMEN
Cryptococcosis therapy is often limited by toxicity problems, antifungal tolerance, and high costs. Studies approaching chalcogen compounds, especially those containing selenium, have shown promising antifungal activity against pathogenic species. This work aimed to evaluate the in vitro and in vivo antifungal potential of organoselenium compounds against Cryptococcus neoformans. The lead compound LQA_78 had an inhibitory effect on C. neoformans planktonic cells and dispersed cells from mature biofilms at similar concentrations. The fungal growth inhibition led to an increase in budding cells arrested in the G2/M phase, but the compound did not significantly affect structural cell wall components or chitinase activity, an enzyme that regulates the dynamics of the cell wall. The compound also inhibited titan cell (Tc) and enlarged capsule yeast (NcC) growth and reduced the body diameter and capsule thickness associated with increased capsular permeability of both virulent morphotypes. LQA_78 also reduced fungal melanization through laccase activity inhibition. The fungicidal activity was observed at higher concentrations (16 to 64 µg/mL) and may be associated with augmented plasma membrane permeability, ROS production, and loss of mitochondrial membrane potential. While LQA_78 is a nonhemolytic compound, its cytotoxic effects were cell type dependent, exhibiting no toxicity on Galleria mellonella larvae at a dose ≤46.5 mg/kg. LQA_78 treatment of larvae infected with C. neoformans effectively reduced the fungal burden and inhibited virulent morphotype formation. To conclude, LQA_78 displays fungicidal action and inhibits virulence factors of C. neoformans. Our results highlight the potential use of LQA_78 as a lead molecule for developing novel pharmaceuticals for treating cryptococcosis.
Asunto(s)
Antifúngicos , Cryptococcus neoformans , Animales , Antifúngicos/uso terapéutico , Cryptococcus neoformans/efectos de los fármacos , Larva/efectos de los fármacos , Larva/microbiología , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/microbiología , Factores de Virulencia/metabolismoRESUMEN
DNA-targeting agents have a significant clinical use, although toxicity remains an issue that plays against their widespread application. Understanding the mechanism of action and DNA damage response elicited by such compounds might contribute to the improvement of their use in anticancer chemotherapy. In a previous study, our research group characterized a new DNA-targeting agent - pradimicin-IRD. Since DNA-targeting agents and DNA repair are close-related subjects, the present study used in silico-modelling and a transcriptomic approach seeking to characterize the DNA repair pathways activated in HCT 116 cells following pradimicin-IRD treatment. Molecular docking analysis showed pradimicin-IRD as a DNA intercalating agent and a potential inhibitor of DNA-binding proteins. Furthermore, the transcriptomic study highlighted DNA repair functions related to genes modulated by pradimicin-IRD, such as nucleotide excision repair, telomeres maintenance and double-strand break repair. When validating these functions, PCNA protein levels decreased after exposure to pradimicin. Furthermore, molecular docking analysis suggested DNA-pradimicin-PCNA interaction. In addition, hTERT and POLH showed reduced mRNA levels after 6 h of treatment with pradimicin-IRD. Moreover, POLH-deficient cells displayed higher resistance to pradimicin-IRD than POLH-proficient cells and the compound prevented formation of the POLH/DNA complex (molecular docking). Since the modulation of DNA repair genes by pradimicin-IRD is TP53-independent, unlike doxorubicin, dissimilarities between the mechanism of action and the DNA damage response of pradimicin-IRD and doxorubicin open new insights for further studies of pradimicin-IRD as a new antineoplastic compound.
Asunto(s)
Antineoplásicos , Humanos , Simulación del Acoplamiento Molecular , Antígeno Nuclear de Célula en Proliferación , Antineoplásicos/farmacología , Reparación del ADN , ADN , Doxorrubicina/farmacología , Daño del ADNRESUMEN
AIMS: Colorectal cancer (CRC) is a very heterogeneous disease. One of its hallmarks is the dysregulation of protein kinases, which leads to molecular events related to carcinogenesis. Hence, kinase inhibitors have been developed and are a new strategy with promising potential for CRC therapy. This study aims to explore AD80, a multikinase inhibitor, as a drug option for CRC, with evaluation of the PI3K/AKT/mTOR and MAPK (ERK1/2) status of CRC cells' panel and the cytotoxicity of AD80 in those cells, as well as in normal colon cells. MAIN METHODS: Cellular and molecular mechanisms, such as clonogenicity, cell cycle, morphology, protein and mRNA expression, were investigated in CRC cells after AD80 exposure. KEY FINDINGS: Results show that PI3K/AKT/mTOR and MAPK signaling pathways are upregulated in CRC cellular models, with increased phosphorylation of mTOR, P70S6K, S6RP, 4EBP1, and ERK1/2. Hence, AD80 selectively reduces cell viability of CRC cells. Therefore, the antitumor mechanisms of AD80, such as clonogenicity inhibition (reduction of colony number and size), G2/M arrest (increased G2/M population, and CDKN1B mRNA expression), DNA damage (increased H2AX and ERK1/2 phosphorylation, and CDKN1A and GADD45A mRNA expression), apoptosis (increased PARP1 cleavage, and BAX, PMAIP1, BBC3 mRNA expression) and inhibition of S6RP phosphorylation were validated in CRC model. SIGNIFICANCE: Our findings reinforce kinases as promising cancer therapeutic targets for the treatment of colorectal cancer, suggesting AD80 as a drug candidate.
Asunto(s)
Neoplasias Colorrectales , Proteínas Quinasas S6 Ribosómicas 70-kDa , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteína X Asociada a bcl-2RESUMEN
Cyclotides are mini-proteins with potent bioactivities and outstanding potential for agricultural and pharmaceutical applications. More than 450 different plant cyclotides have been isolated from six angiosperm families. In Brazil, studies involving this class of natural products are still scarce, despite its rich floristic diversity. Herein were investigated the cyclotides from Anchietea pyrifolia roots, a South American medicinal plant from the family Violaceae. Fourteen putative cyclotides were annotated by LC-MS. Among these, three new bracelet cyclotides, anpy A-C, and the known cycloviolacins O4 (cyO4) and O17 (cyO17) were sequenced through a combination of chemical and enzymatic reactions followed by MALDI-MS/MS analysis. Their cytotoxic activity was evaluated by a cytotoxicity assay against three human cancer cell lines (colorectal carcinoma cells: HCT 116 and HCT 116 TP53-/- and breast adenocarcinoma, MCF 7). For all assays, the IC50 values of isolated compounds ranged between 0.8 and 7.3 µM. CyO17 was the most potent cyclotide for the colorectal cancer cell lines (IC50, 0.8 and 1.2 µM). Furthermore, the hemolytic activity of anpy A and B, cyO4, and cyO17 was assessed, and the cycloviolacins were the least hemolytic (HD50 > 156 µM). This work sheds light on the cytotoxic effects of the anpy cyclotides against cancer cells. Moreover, this study expands the number of cyclotides obtained to date from Brazilian plant biodiversity and adds one more genus containing these molecules to the list of the Violaceae family.
Asunto(s)
Productos Biológicos , Ciclotidas , Proteínas de Plantas , Violaceae , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Brasil , Línea Celular Tumoral , Ciclotidas/química , Ciclotidas/aislamiento & purificación , Ciclotidas/farmacología , Humanos , Proteínas de Plantas/química , Proteínas de Plantas/aislamiento & purificación , Proteínas de Plantas/farmacología , Espectrometría de Masas en Tándem , Violaceae/químicaRESUMEN
Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis. In addition, structure-activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC50 values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC50: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.
Asunto(s)
Antineoplásicos/farmacología , Cinamatos/farmacología , Histona Desacetilasa 1/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cinamatos/síntesis química , Cinamatos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation between DNA repair deficiency and the increased effect of DNA targeting agents highlights the double-strand break (DSB) repair, which comprises the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. The DNA targeting agents are classified into two major groups: non-covalent DNA binding agents and covalent DNA-reactive agents. Although these agents have well-known limitations, such as resistance and secondary carcinogenesis risk, they are extremely important in today's real-life cancer therapy in combination with targeted therapy and immunotherapy. Indeed, DNA targeting drugs are promising therapeutics with a precise application through the background of cancer-specific DNA repair failure. In the current review, the mechanisms of action of diversified DNA-targeting agents, as well as the modulation of DNA repair pathways to increase the DNA-damaging drugs efficacy are presented. Finally, DNA-targeting-based therapies are discussed considering risks, resistance and its uses in the medicine precision era.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinogénesis , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Humanos , Medicina de Precisión , Factores de RiesgoRESUMEN
BACKGROUND: Effective cancer treatment is a major public health challenge. The limitations of current therapies and their adverse effects reduce the efficacy of treatment, leading to significant mortality rates worldwide. Moreover, natural product chemistry occupies a prominent role in the search for new treatment alternatives, by contributing a spectrum of chemical structures that may potentially yield new bioactive compounds. The compound [6]-gingerol (1) is the main active substance in ginger (Zingiber officinale) and several studies have shown it to produce beneficial effects, including antitumor activity. OBJECTIVE: This work aims to obtain new gingerol derivatives with cytotoxic activity. METHODS: [6]-gingerol was isolated and its derivatives were produced using click chemistry, obtaining eight new compounds. All chemical structures were determined by means of IR, NMR and HRMS data, and cytotoxicity was evaluated in the HCT 116 (colon carcinoma) and MCF-7 (breast carcinoma) cell lines at concentrations of 5 µmol L-1 and 50 µmol L-1. RESULTS: At 50 µmol L-1, more than 70% inhibition of cell growth was achieved with compounds 2e, 2g against HCT 116, and 2b, 2d, 2e, 2f and 2g against MCF-7. CONCLUSION: The obtained compounds showed only moderate cytotoxic activity. However, the products with substituents occupying the meta position in relation to the triazole ring showed increased cytotoxic properties. The brominated compound (2g) showed the strongest activity, inhibiting cell proliferation by 87%.