RESUMEN

Trans-chalcone (TC) is a flavonoid precursor characterized by a wide spectrum of action, with anti-inflammatory and antioxidant effects. However, no validated methods are available in official compendia for the analysis of this substance. Thus, the aim of this work was to develop and validate a simple, fast, and reproducible spectrophotometric method for the analysis of TC in raw material, and in topical pharmaceutical formulation containing TC. The established conditions were: methanol as extracting solvent, and detection wavelength of 309 nm by UV spectrophotometer. All tests followed the rules of Resolution RDC 166, 2017. The proposed method was selective. Linearity was demonstrated in the concentration range of 1 to 8 µg/mL (r = 0.999). Repeatability and intermediate precision were confirmed by low relative standard deviation values of 1.53% and 2.70% for TC, and of 1.73% and 2.91% for formulation containing TC. Accuracy, evaluated through recovery test, was adequate, with minimum of 98.24% and maximum of 100.23% of recovery. It was observed that the small deliberate modifications done did not interfere with the results, demonstrating the method is robust. The results showed that the method was considered suitable for the intended purpose, inexpensive, easy to apply, selective, linear, precise, accurate, and robust for the determination TC, and pharmaceutical formulation containing TC. Thus, the method developed satisfies the need for an analytical method for the determination of TC, and topical formulation containing TC, being effective, innovative and able to aid in the development of the pharmaceutical field.

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Trans-chalcona (TC) é um precursor de flavonoides caracterizado por um amplo espectro de ação, como efeitos anti-inflamatórios e antioxidantes. No entanto, não há método validado disponível em compêndio oficial para análise deste composto. Então, o objetivo deste trabalho foi desenvolver e validar um método espectrofotométrico, simples, rápido e reprodutível para análise de TC em matéria-prima, e em formulação farmacêutica tópica contendo TC. As condições estabelecidas foram: metanol como o solvente de extração, e detecção no comprimento de onda de 309 nm por espectrofotometria no UV. Todos os testes seguiram as normas da RDC 166, 2017. O método proposto foi seletivo. A linearidade foi demonstrada na faixa de concentração de 1 a 8 µg/mL (r = 0.999). A repetibilidade e a precisão intermediária foram confirmadas pelos valores baixos de desvio padrão relativo de 1,53% e 2,70% para a TC, e de 1,73% e 2,91% para a formulação contendo TC. A exatidão, avaliada por meio de testes de recuperação, foi adequada, com mínimo de 98,24% e máximo de 100,04% de recuperação. Observou-se que pequenas modificações no método não interferiram nos resultados, demonstrando que o método é robusto. Os resultados demonstraram que o método foi adequado para a finalidade pretendida, barato, de fácil aplicação, seletivo, linear, preciso, exato e robusto para determinação de TC, e de formulação contendo TC. Então o método desenvolvido satisfaz as necessidades de um método analítico para determinação de TC, e de formulação tópica contendo TC, e é eficaz, inovador e pode contribuir para o desenvolvimento da área farmacêutica.

RESUMEN

Ampelozizyphus amazonicus Ducke, known as "saracura-mirá" in the Amazon rainforest, is valued for its traditional use in malaria prevention and treatment. The plant's roots and bark are employed for these purposes, while the wood is often overlooked. Given the global importance of leishmaniasis, research focused on A. amazonicus anti-Leishmania amazonensis potential. The ethyl acetate extract from the bark (EAEB) exhibited the most effective inhibition of intracellular amastigote growth with IC50 7.0 µg.mL-1 but showed high toxicity (CC50 9.0 µg.mL-1). The wood ethanol (EW) and ethyl acetate (EAEW) extracts demonstrated promising results against L. amazonensis with IC50 15.8 µg.mL-1 and 10.0 µg.mL-1, CC50 50.5 µg.mL-1 and 22.7 µg.mL-1, respectively. High-speed countercurrent chromatography combined with mass spectrometry  off-line detection was employed for the bioassay-guided fractionation of EAEB and EAEW using HEMWat as solvent system. These extracts showed to be rich in saponins and triterpenes, besides minor glycosylated flavonoids. HSCCC was effective in obtaining high purity fractions, leading to the identification of a di-glycosylated triterpene saponin from EAEB, and melaleucic acid from EAEW. These findings highlight A. amazonicus as a potential source for developing new therapeutic alternatives for leishmaniasis and HSCCC as a technique enabling better separation efficiency of complex saponin matrices.

RESUMEN

Chalcone represents a vital biosynthetic scaffold owing to its numerous therapeutic effects. The present study was intended to synthesize 17 chalcone derivatives (3a-q) by direct coupling of substituted acetophenones and benzaldehyde. The target chalcones were characterized by spectroscopic analyses followed by their in vitro antimicrobial, and antileishmanial investigations with reference to standard drugs. The majority of the chalcones displayed good to excellent biological activities. Chalcone 3q (1000 µg ml-1) exhibited the most potent antibacterial effect with its zone of inhibition values of 30, 33 and 34 mm versus Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa respectively. The results also confirmed chalcone 3q to be the most potent versus Leishmania major with the lowest IC50 value of 0.59 ± 0.12 µg ml-1. Chalcone 3i (500 µg ml-1) was noticed to be the most potent antifungal agent with its zone of inhibition being 29 mm against Candida albicans. Computational studies of chalcones 3i and 3q supported the preliminary in vivo results. The existence of the amino moiety and bromine atom on ring-A and methoxy moieties on ring-B caused better biological effects of the chalcones. In brief, the investigations reveal that chalcones (3i and 3q) can be employed as building blocks to discover novel antimicrobial agents.

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 10 µM in HCT 116 cells and above 20 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

Drug-resistant bacteria constitute a big barrier against current pharmacotherapy. Efforts are urgent to discover antibacterial drugs with novel chemical and biological features. Our work aimed at the synthesis, evaluation of antibacterial effects, and toxicity of licochalcone C (LCC), a naturally occurring chalcone. The synthetic route included six steps, affording a 10% overall yield. LCC showed effects against Gram-positive bacteria (MIC = 6.2-50.0 µg/mL), Mycobacterium species (MIC = 36.2-125 µg/mL), and Helicobacter pylori (MIC = 25 µg/mL). LCC inhibited the biofilm formation of MSSA and MRSA, demonstrating MBIC50 values of 6.25 µg/mL for both strains. The investigations by fluorescence microscopy, using PI and SYTO9 as fluorophores, indicated that LCC was able to disrupt the S. aureus membrane, similarly to nisin. Systemic toxicity assays using Galleria mellonella larvae showed that LCC was not lethal at 100 µg/mL after 80 h treatment. These data suggest new uses for LCC as a compound with potential applications in antibacterial drug discovery and medical device coating.

RESUMEN

OBJECTIVES: This work investigated the acute antinociceptive effect of a synthetic chalcone, 4-dimethylamino chalcone (DMAC), as well as its effects on vincristine-induced peripheral neuropathy (VIPN) in mice. METHODS: The inhibitory activity of myeloperoxidase was assessed by measuring HOCl formation. Formalin and hot plate tests were used to study the acute antinociceptive effect of DMAC. VIPN was induced through the administration of vincristine sulphate (0.1 mg/kg, i.p., 14 days). Then, DMSO, DMAC (10 or 30 mg/kg; i.p.), or pregabalin (10 mg/kg, i.p.) were administered for 14 consecutive days. Thermal hyperalgesia and mechanical allodynia were evaluated before and after VIPN induction and on days 1, 3, 7, and 14 of treatment. Neurodegeneration and neuroinflammation were assessed through immunohistochemistry for NF200, iNOS, and arginase-1 within the sciatic nerve. KEY FINDINGS: DMAC inhibited myeloperoxidase activity in vitro and presented an acute antinociceptive effect in both formalin and hot plate tests, with the involvement of muscarinic and opioid receptors. Treatment with 30 mg/kg of DMAC significantly attenuated thermal hyperalgesia and mechanical allodynia and prevented macrophage proinflammatory polarisation in VIPN mice. CONCLUSIONS: Our results show that DMAC, acting through different mechanisms, effectively attenuates VIPN.

Asunto(s)

Analgésicos , Chalconas , Hiperalgesia , Neuralgia , Peroxidasa , Animales , Ratones , Masculino , Analgésicos/farmacología , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Peroxidasa/metabolismo , Chalconas/farmacología , Vincristina/farmacología , Modelos Animales de Enfermedad , Dolor Agudo/tratamiento farmacológico , Nervio Ciático/efectos de los fármacos

RESUMEN

The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96 h of exposure. In behavioral tests, CHALCNM (40 mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20 mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75 Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.

Asunto(s)

Ansiolíticos , Conducta Animal , Chalcona , Pez Cebra , Animales , Conducta Animal/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Chalcona/análogos & derivados , Ansiolíticos/farmacología , Ansiolíticos/química , Ansiolíticos/síntesis química , Receptores de GABA-A/metabolismo , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacología , Estructura Molecular , Simulación del Acoplamiento Molecular , Chalconas/farmacología , Chalconas/química , Chalconas/síntesis química , Locomoción/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

Breast cancer (BC) is one of the most common cancers among women. Effective treatment requires precise tailoring to the genetic makeup of the cancer for improved efficacy. Numerous research studies have concentrated on natural compounds and their anti-breast cancer properties to improve the existing treatment options. Chromolaena tacotana (Klatt) R.M. King and H. Rob (Ch. tacotana) is a notable source of bioactive hydroxy-methylated flavonoids. However, the specific anti-BC mechanisms of these flavonoids, particularly those present in the plant's inflorescences, remain partly undefined. This study focuses on assessing a chalcone derivative extracted from Ch. tacotana inflorescences for its potential to concurrently activate regulated autophagy and intrinsic apoptosis in luminal A and triple-negative BC cells. We determined the chemical composition of the chalcone using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy. Its selective cytotoxicity against BC cell lines was assessed using the MTT assay. Flow cytometry and Western blot analysis were employed to examine the modulation of proteins governing autophagy and the intrinsic apoptosis pathway. Additionally, in silico simulations were conducted to predict interactions between chalcone and various anti-apoptotic proteins, including the mTOR protein. Chalcone was identified as 2',4-dihydroxy-4',6'-dimethoxy-chalcone (DDC). This compound demonstrated a selective inhibition of BC cell proliferation and triggered autophagy and intrinsic apoptosis. It induced cell cycle arrest in the G0/G1 phase and altered mitochondrial outer membrane potential (∆ψm). The study detected the activation of autophagic LC3-II and mitochondrial pro-apoptotic proteins in both BC cell lines. The regulation of Bcl-XL and Bcl-2 proteins varied according to the BC subtype, yet they showed promising molecular interactions with DDC. Among the examined pro-survival proteins, mTOR and Mcl-1 exhibited the most favorable binding energies and were downregulated in BC cell lines. Further research is needed to fully understand the molecular dynamics involved in the activation and interaction of autophagy and apoptosis pathways in cancer cells in response to potential anticancer agents, like the hydroxy-methylated flavonoids from Ch. tacotana.

RESUMEN

The development of novel phytotoxic compounds has been an important aim of weed control research. In this study, we synthesized fluorinated chalcone derivatives featuring both electron-donating and electron-withdrawing groups. These compounds were evaluated both as inhibitors of the photosystem II (PSII) electron chain as well as inhibitors of the germination and seedling growth of Amaranthus plants. Chlorophyll a (Chl a) fluorescence assay was employed to evaluate their effects on PSII, while germination experiments were conducted to assess their impact on germination and seedling development. The results revealed promising herbicidal activity for (E)-3-(4-bromophenyl)-1-(4-fluorophenyl)prop-2-en-1-one (7 a) and (E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one (7 e). Compounds 7 a and 7 e exhibited a reduction in Chl a parameters associated with performance indexes and electron transport per reaction center. This reduction suggests a decrease in PSII activity, attributed to the blockage of electron flow at the quinone pool. Molecular docking analyses of chalcone derivatives with the D1 protein of PSII revealed a stable binding conformation, wherein the carbonyl and fluorine groups interacted with Phe265 and His215 residues, respectively. Additionally, at a concentration of 100 µM, compound 7 e demonstrated pre- and post-emergent herbicidal activity, resulting in a reduction of the seed germination index, radicle and hypocotyl lengths of Amaranthus weeds.

Asunto(s)

Amaranthus , Chalconas , Herbicidas , Plantones , Complejo de Proteína del Fotosistema II , Chalconas/farmacología , Simulación del Acoplamiento Molecular , Inhibidores de Crecimiento/farmacología , Clorofila A , Herbicidas/química , Malezas , Clorofila

RESUMEN

BACKGROUND: Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system. OBJECTIVES: This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa). METHODS: Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1 , 5-HTR2A/2C , and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration. RESULTS: As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively. CONCLUSION: Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Asunto(s)

Ansiolíticos , Chalcona , Chalconas , Animales , Ansiolíticos/farmacología , Pez Cebra , Simulación del Acoplamiento Molecular , Serotonina , Benzodiazepinas , Receptores de GABA-A

RESUMEN

Chalcones have an open chain flavonoid structure that can be obtained from natural sources or by synthesis and are widely distributed in fruits, vegetables, and tea. They have a simple and easy to handle structure due to the α-ß-unsaturated bridge responsible for most biological activities. The facility to synthesize chalcones combined with its efficient in combating serious bacterial infections make these compounds important agents in the fight against microorganisms. In this work, the chalcone (E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (HDZPNB) was characterized by spectroscopy and electronic methods. In addition, microbiological tests were performed to investigate the modulator potential and efflux pump inhibition on S. aureus multi-resistant strains. The modulating effect of HDZPNB chalcone in association with the antibiotic norfloxacin, on the resistance of the S. aureus 1199 strain, resulted in increase the MIC. In addition, when HDZPNB was associated with ethidium bromide (EB), it caused an increase in the MIC value, thus not inhibiting the efflux pump. For the strain of S. aureus 1199B, carrying the NorA pump, the HDZPNB associated with norfloxacin showed no modulatory, and when the chalcone was used in association with EB, it had no inhibitory effect on the efflux pump. For the tested strain of S. aureus K2068, which carries the MepA pump, it can be observed that the chalcone together the antibiotic resulted in an increase the MIC. On the other hand, when chalcone was used in association with EB, it caused a decrease in bromide MIC, equal to the reduction caused by standard inhibitors. Thus, these results indicate that the HDZPNB could also act as an inhibitor of the S. aureus gene overexpressing pump MepA. The molecular docking reveals that chalcone has a good binding energies -7.9 for HDZPNB/MepA complexes, molecular dynamics simulations showed that Chalcone/MetA complexes showed good stability of the structure in an aqueous solution, and ADMET study showed that the chalcone has a good oral bioavailability, high passive permeability, low risk of efflux, low clearance rate and low toxic risk by ingestion. The microbiological tests show that the chalcone can be used as a possible inhibitor of the Mep A efflux pump.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Chalcona , Chalconas , Nitrofenoles , Antibacterianos/química , Staphylococcus aureus , Norfloxacino/farmacología , Norfloxacino/metabolismo , Simulación del Acoplamiento Molecular , Chalcona/farmacología , Chalconas/farmacología , Pruebas de Sensibilidad Microbiana , Etidio/metabolismo , Proteínas Bacterianas/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos

RESUMEN

Aim: Our objective was to investigate the trypanocidal effect of the chalcone (2E,4E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one (CPNC). Material & methods: Cytotoxicity toward LLC-MK2 host cells was assessed by MTT assay, and the effect on Trypanosoma cruzi life forms (epimastigotes, trypomastigotes and amastigotes) was evaluated by counting. Flow cytometry analysis was performed to evaluate the possible mechanisms of action. Finally, molecular docking simulations were performed to evaluate interactions between CPNC and T. cruzi enzymes. Results: CPNC showed activity against epimastigote, trypomastigote and amastigote life forms, induced membrane damage, increased cytoplasmic reactive oxygen species and mitochondrial dysfunction on T. cruzi. Regarding molecular docking, CPNC interacted with both trypanothione reductase and TcCr enzymes. Conclusion: CPNC presented a trypanocidal effect, and its effect is related to oxidative stress, mitochondrial impairment and necrosis.

Asunto(s)

Enfermedad de Chagas , Chalconas , Tripanocidas , Trypanosoma cruzi , Humanos , Chalconas/farmacología , Simulación del Acoplamiento Molecular , Enfermedad de Chagas/tratamiento farmacológico , Especies Reactivas de Oxígeno , Tripanocidas/farmacología

RESUMEN

Peanut (Arachis hypogaea) and its wild relatives are among the few species that naturally synthesize resveratrol, a well-known stilbenoid phytoalexin that plays a crucial role in plant defense against biotic and abiotic stresses. Resveratrol has received considerable attention due to its health benefits, such as preventing and treating various human diseases and disorders. Chalcone (CHS) and Stilbene (STS) Synthases are plant-specific type III Polyketide Synthases (PKSs) that share the same substrates and are key branch enzymes in the biosynthesis of flavonoids and stilbenoids, respectively. Although resveratrol accumulation in response to external stimulus has been described in peanut, there are no comprehensive studies of the CHS and STS gene families in the genus Arachis. In the present study, we identified and characterized 6 CHS and 46 STS genes in the tetraploid peanut and an average of 4 CHS and 22 STS genes in three diploid wild species (Arachis duranensis, Arachis ipaënsis and Arachis stenosperma). The CHS and STS gene and protein structures, chromosomal distributions, phylogenetic relationships, conserved amino acid domains, and cis-acting elements in the promoter regions were described for all Arachis species studied. Based on gene expression patterns of wild A. stenosperma STS genes in response to different biotic and abiotic stresses, we selected the candidate AsSTS4 gene, which is strongly induced by ultraviolet (UV) light exposure, for further functional investigation. The AsSTS4 overexpression in peanut hairy roots significantly reduced (47%) root-knot nematode infection, confirming that stilbene synthesis activation in transgenic plants can increase resistance to pathogens. These findings contribute to understanding the role of resveratrol in stress responses in Arachis species and provide the basis for genetic engineering for improved production of valuable secondary metabolites in plants.

Asunto(s)

Arachis , Fabaceae , Humanos , Arachis/genética , Arachis/metabolismo , Estudio de Asociación del Genoma Completo , Filogenia , Resveratrol/metabolismo , Fabaceae/genética

RESUMEN

Based on previous results with benzoindazolequinone (BIZQ) and 3-methylnaphtho [2,3-d]isoxazole-4,9-quinone (NIQ) derivatives, a novel series of chalcone-1,4-naphthoquinone/benzohydroquinone (CNQ and CBHQ) compounds were synthesized from 2-acetyl-5,8-dihydro-6-(4-methyl-3-pentenyl)-1,4-naphthohydroquinone. Their structures were elucidated via spectroscopy. These hybrids were assessed in vivo for their antiproliferative activity on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, revealing cytotoxicity with IC50 values between 6.0 and 110.5 µM. CBHQ hybrids 5e and 5f displayed enhanced cytotoxicity against both cell lines, whereas CNQ hybrids 6a-c and 6e exhibited higher cytotoxic activity against MCF-7 cells. Docking studies showed strong binding energies (ΔGbin) of CNQs to kinase proteins involved in carcinogenic pathways. Furthermore, our in silico analysis of drug absorption, distribution, metabolism, and excretion (ADME) properties suggests their potential as candidates for cancer pre-clinical assays.

Asunto(s)

Antineoplásicos , Chalconas , Humanos , Chalconas/farmacología , Chalconas/química , Estructura Molecular , Relación Estructura-Actividad , Proliferación Celular , Células MCF-7 , Antineoplásicos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Línea Celular Tumoral

RESUMEN

Chromolaena tacotana (Klatt) R. M. King and H. Rob (Ch. tacotana) contains bioactive flavonoids that may have antioxidant and/or anti-cancer properties. This study investigated the potential anti-cancer properties of a newly identified chalcone isolated from the inflorescences of the plant Chromolaena tacotana (Klatt) R. M. King and H. Rob (Ch. tacotana). The chalcone structure was determined using HPLC/MS (QTOF), UV, and NMR spectroscopy. The compound cytotoxicity and selectivity were evaluated on prostate, cervical, and breast cancer cell lines using the MTT assay. Apoptosis and autophagy induction were assessed through flow cytometry by detecting annexin V/7-AAD, active Casp3/7, and LC3B proteins. These results were supported by Western blot analysis. Mitochondrial effects on membrane potential, as well as levels of pro- and anti-apoptotic proteins were analyzed using flow cytometry, fluorescent microscopy, and Western blot analysis specifically on a triple-negative breast cancer (TNBC) cell line. Furthermore, molecular docking (MD) and molecular dynamics (MD) simulations were performed to evaluate the interaction between the compounds and pro-survival proteins. The compound identified as 2',3,4-trihydroxy-4',6'-dimethoxy chalcone inhibited the cancer cell line proliferation and induced apoptosis and autophagy. MDA-MB-231, a TNBC cell line, exhibited the highest sensitivity to the compound with good selectivity. This activity was associated with the regulation of mitochondrial membrane potential, activation of the pro-apoptotic proteins, and reduction of anti-apoptotic proteins, thereby triggering the intrinsic apoptotic pathway. The chalcone consistently interacted with anti-apoptotic proteins, particularly the Bcl-2 protein, throughout the simulation period. However, there was a noticeable conformational shift observed with the negative autophagy regulator mTOR protein. Future studies should focus on the molecular mechanisms underlying the anti-cancer potential of the new chalcone and other flavonoids from Ch. tacotana, particularly against predominant cancer cell types.

Asunto(s)

Chalcona , Chalconas , Chromolaena , Neoplasias de la Mama Triple Negativas , Humanos , Chalcona/farmacología , Chalconas/farmacología , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Neoplasias de la Mama Triple Negativas/metabolismo , Proliferación Celular , Apoptosis

RESUMEN

Chagas disease (CD) is a neglected tropical disease of worldwide health concern, caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi), endemic in Latin America and present in North America and Europe. The WHO recommended drug for CD, benznidazole has low safety profile and several limitations. Therefore, an entity with better therapeutic potential to treat CD is required. Chalcones are an important class of compounds, which have shown antichagasic potential. Thus, the objective of this study was to evaluate the activity of synthetic p-aminochalcones against T. cruzi. Chalcones 1 and 2 were synthesized by Claisen-Schmidt condensation and characterized by both spectroscopic and theoretical methods. Initially, they were submitted to molecular docking simulations using cruzain and trypanothione reductase (TR) enzymes. It was expected to observe the possible interactions of chalcones with the catalytic site and other important regions of these main pharmacological targets of T. cruzi. Their cytotoxicity within host cells were assessed by MTT reduction assay using LLC-MK2 cells, with CC50 = 85.6 ± 9.2 µM and 1115 ± 381.7 µM for chalcones 1 and 2, respectively. These molecules were also tested against epimastigote and trypomastigote life forms of T. cruzi, causing reduction in the number of viable parasites. For the evaluation of the effect on intracellular amastigotes, infected LLC-MK2 cells were incubated with the chalcones for 24 h, causing reduction in the percentage of infected cells and the number of amastigotes/100 cells. Finally, flow cytometry assays were performed for analyzing cell death mechanisms (7-AAD/AxPE labelling), cytoplasmic ROS accumulation (DCFH-DA assay) and mitochondrial transmembrane potential disruption (Rho123 assay). Both chalcones (1 and 2) caused membrane damage, ROS accumulation and mitochondrial depolarization. In conclusion, the synthetic p-aminochalcones presented trypanocidal effect, causing membrane damage and oxidative stress. Their mechanism of action may be related to cruzain and TR inhibition.

Asunto(s)

Enfermedad de Chagas , Chalconas , Tripanocidas , Trypanosoma cruzi , Humanos , Tripanocidas/química , Especies Reactivas de Oxígeno , Simulación del Acoplamiento Molecular , Chalconas/farmacología , Chalconas/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico

RESUMEN

Breast cancer is responsible for 25% of all cancers that affect women. Due to its high heterogeneity pattern in clinical diagnosis and its molecular profile differences, researchers have been seeking new targets and therapies, with more specificity and fewer side effects. Thus, one compound that has garnered our attention is trans-chalcone, which is naturally occurring in various plants and possesses promising biological properties, including antitumor effects. MiRNA is an extensive class of non-coding small, endogenous, and single-stranded RNAs, and it is involved in post-translational gene regulation. Therefore, the objective of this study was to investigate the effects of TChal on miRNAs expression and its relationship with anticancer activity against MCF-7. Initially, the trans-chalcone IC50 value was established by MTT assay for MCF-7and HaCat (non-cancer cell), in which we found out that it was 53.73 and 44.18 µM, respectively. Subsequently, we treated MCF-7 cells with trans-chalcone at its IC50 concentration and performed Mi-seq analysis, which unveiled 23 differentially expressed miRNAs. From this set, we selected five miRNAs (miR-25-5p, miR-27a-3p, miR-891a, miR-449a, and miR-4485) for further validation using qRT-PCR, guided by in silico analysis and their known association with tumorigenesis. In conclusion, our research provides valuable insights into the potential use of TChal to reveal MicroRNAs molecular targets that can be applied in breast cancer therapy.

Asunto(s)

Neoplasias de la Mama , Chalconas , MicroARNs , Humanos , Femenino , MicroARNs/genética , MicroARNs/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Células MCF-7 , Chalconas/farmacología , Chalconas/uso terapéutico , Regulación Neoplásica de la Expresión Génica

RESUMEN

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and ß rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC (A) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C-K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.

Asunto(s)

Antineoplásicos , Chalcona , Chalconas , Humanos , Células MCF-7 , Chalcona/farmacología , Chalconas/química , Cinamatos/farmacología , Antineoplásicos/química , Piridinas/farmacología , Proliferación Celular , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Aim: To access the metabolic changes caused by a chalcone derivative (LabMol-75) through a proteomic approach. Methods: Proteomic analysis was performed after 9 h of Paracoccidioides brasiliensis yeast (Pb18) cell incubation with the LabMol-75 at MIC. The proteomic findings were validated through in vitro and in silico assays. Results: Exposure to the compound led to the downregulation of proteins associated with glycolysis and gluconeogenesis, ß-oxidation, the citrate cycle and the electron transport chain. Conclusion: LabMol-75 caused an energetic imbalance in the fungus metabolism and deep oxidative stress. Additionally, the in silico molecular docking approach pointed to this molecule as a putative competitive inhibitor of DHPS.

Asunto(s)

Paracoccidioides , Paracoccidioidomicosis , Paracoccidioides/metabolismo , Proteómica , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Oxidación-Reducción , Paracoccidioidomicosis/microbiología

RESUMEN

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.