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1.
Int J Mol Sci ; 25(8)2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38674101

RESUMO

Betulonic acid (B(O)A) is a pentacyclic lupane-type triterpenoid that widely exists in plants. There are scientific reports indicating anticancer activity of B(O)A, as well as the amides and esters of this triterpenoid. In the first step of the study, the synthesis of novel amide derivatives of B(O)A containing an acetylenic moiety was developed. Subsequently, the medium-soluble compounds (EB171 and EB173) and the parent compound, i.e., B(O)A, were investigated for potential cytotoxic activity against breast cancer (MCF-7 and MDA-MB-231) and melanoma (C32, COLO 829 and A375) cell lines, as well as normal human fibroblasts. Screening analysis using the WST-1 test was applied. Moreover, the lipophilicity and ADME parameters of the obtained derivatives were determined using experimental and in silico methods. The toxicity assay using zebrafish embryos and larvae was also performed. The study showed that the compound EB171 exhibited a significant cytotoxic effect on cancer cell lines: MCF-7, A-375 and COLO 829, while it did not affect the survival of normal cells. Moreover, studies on embryos and larvae showed no toxicity of EB171 in an animal model. Compared to EB171, the compound EB173 had a weaker effect on all tested cancer cell lines and produced less desirable effects against normal cells. The results of the WST-1 assay obtained for B(O)A revealed its strong cytotoxic activity on the examined cancer cell lines, but also on normal cells. In conclusion, this article describes new derivatives of betulonic acid-from synthesis to biological properties. The results allowed to indicate a promising direction for the functionalization of B(O)A to obtain derivatives with selective anticancer activity and low toxicity.


Assuntos
Amidas , Antineoplásicos , Ácido Betulínico , Ácido Oleanólico , Peixe-Zebra , Humanos , Animais , Amidas/química , Amidas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Ácido Oleanólico/química , Ácido Oleanólico/síntese química , Ácido Oleanólico/farmacocinética , Linhagem Celular Tumoral , Simulação por Computador , Células MCF-7 , Sobrevivência Celular/efeitos dos fármacos
2.
Nutrients ; 15(24)2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38140361

RESUMO

The planetary health diet is a proposition of a diet that is healthy for both people and the environment. The aim of this study was to investigate the nutritional behaviours among people who follow the planetary health diet and those who do not and assess the source of motivation that drives a willingness to follow sustainable diet guidelines. Using a self-administered questionnaire, data were collected from Polish adult volunteers. For analysis, respondents were divided into the following two groups: those following a planetary health diet (PD) and those who were not (O). Of the 216 respondents, 39.4% followed the PD. Non-adherence to the PD was linked to a higher prevalence of overweight and obesity. Taste was the most important factor for both groups during grocery shopping. However, sustainable agriculture and the health benefits of products were significantly more important for the PD followers. It can be concluded that adherence to the planetary diet is associated with lower body mass. This highlights the need for increased awareness and education about a diet's health benefits and environmental impact.


Assuntos
Motivação , Estado Nutricional , Adulto , Humanos , Estudos Transversais , Intenção , Dieta
3.
Curr Issues Mol Biol ; 45(12): 9961-9975, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38132468

RESUMO

Betulin derivatives are proposed to serve as an alternative to the drugs already established in oncologic treatment. Drug-induced nephrotoxicity leading to acute kidney injury frequently accompanies cancer treatment, and thus there is a need to research the effects of betulin derivatives on renal cells. The objective of our study was to assess the influence of the betulin derivatives 28-propynylobetulin (EB5) and 29-diethoxyphosphoryl-28-propynylobetulin (ECH147) on the expression of TGFß1, BMP2 and GDF15 in renal proximal tubule epithelial cells (RPTECs) cultured in vitro. The changes in mRNA expression and copy numbers were assessed using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) and the standard curve method, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the effect of the betulin derivatives on the protein concentration in the culture media's supernatant. The assessment of the betulin derivatives' influence on gene expression demonstrated that the mRNA level and protein concentration did not always correlate with each other. Each of the tested compounds affected the mRNA expression. The RT-qPCR analyses showed that EB5 and ECH147 induced effects similar to those of betulin or cisplatin and resulted in a decrease in the mRNA copy number of all the analyzed genes. The ELISA demonstrated that EB5 and ECH147 elevated the protein concentration of TGFß1 and GDF15, while the level of BMP2 decreased. The concentration of the derivatives used in the treatment was crucial, but the effects did not always exhibit a simple linear dose-dependent relationship. Betulin and its derivatives, EB5 and ECH147, influenced the gene expression of TGFß1, BMP2 and GDF15 in the renal proximal tubule epithelial cells. The observed effects raise the question of whether treatment with these compounds could promote the development of renal fibrosis.

4.
Int J Mol Sci ; 24(22)2023 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-38003677

RESUMO

Due to the incidence of ovarian cancer (OC) and the limitations of available therapeutic strategies, it is necessary to search for novel therapeutic solutions. The aim of this study was to evaluate the cytotoxic effect of betulin 1 and its propynoyl derivatives 2-6 against ovarian cancer cells (SK-OV-3, OVCAR-3) and normal myofibroblasts (18Co). Paclitaxel was used as the reference compound. The propynoyl derivatives 2-6 exhibited stronger antiproliferative and cytotoxic activities compared to betulin 1. In both ovarian cancer cell lines, the most potent compound was 28-propynoylbetulin 2. In the case of compound 2, the calculated IC50 values were 0.2 µM for the SK-OV-3 cells and 0.19 µM for the OVCAR-3 cells. Under the same culture conditions, the calculated IC50 values for compound 6 were 0.26 µM and 0.59 µM, respectively. It was observed that cells treated with compounds 2 and 6 caused a decrease in the potential of the mitochondrial membrane and a significant change in cell morphology. Betulin 1, a diol from the group of pentacyclic triterpenes, has a confirmed wide spectrum of biological effects, including a significant anticancer effect. It is characterized by low bioavailability, which can be improved by introducing changes to its structure. The results showed that chemical modifications of betulin 1 only at position C-28 with the propynoyl group (compound 2) and additionally at position C-3 with the phosphate group (compound 3) or at C-29 with the phosphonate group (compound 6) allowed us to obtain compounds with greater cytotoxic activity than their parent compounds, which could be used to develop novel therapeutic systems effective in the treatment of ovarian cancer.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Triterpenos , Humanos , Feminino , Apoptose , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Triterpenos/farmacologia , Triterpenos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais
5.
Nutrients ; 15(11)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37299391

RESUMO

BACKGROUND: Social isolation during the SARS-CoV-2 pandemic affected people's body weight, therefore, this study was designed to evaluate the association between lifestyle elements and the change in BMI during lockdown. METHODS: This retrospective observational study involved 290 questionnaires completed by adult participants divided into three groups according to BMI change during isolation. The structured questionnaire included a general description of the study objective and collected data regarding sociodemographics, anthropometrics, physical activity, sedentary behaviour, sleep duration, and food intake pre- and during COVID-19 lockdown. RESULTS: A decrease or increase in BMI was found in 23.6% and 47.8% of women and 18.5% and 42.6% of men, respectively. Among those who lost weight, 46.5% of women and 40% of men followed a diet of their own choice, 30.2% of women and 25% of men changed their product mix and reduced their intake, 40% of men stopped eating outside the home. An increase in BMI was associated with increased food intake (32.2% of women and 28.3% of men), increased sleep duration on weekdays (49.2% of women and 43.5% of men) and, in more than 50% of subjects, decreased physical activity. In women, increased BMI was associated with the highest frequency of snacking (p = 0.0003), the highest intake of sweets (p = 0.0021), and in men with the highest intake of alcohol (p = 0.0017). CONCLUSIONS: The observed changes in BMI during social isolation were the result of lifestyle modifications including dietary behaviour and differed by gender.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Masculino , Humanos , Feminino , COVID-19/epidemiologia , Índice de Massa Corporal , Pandemias , Polônia/epidemiologia , Comportamento Alimentar , Controle de Doenças Transmissíveis , Estilo de Vida
6.
Pharmaceutics ; 14(11)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36365190

RESUMO

Pentacyclic triterpenes, including betulin, are widespread natural products with various pharmacological effects. These compounds are the starting material for the synthesis of substances with promising anticancer activity. The chemical modification of the betulin scaffold that was carried out as part of the research consisted of introducing the indole moiety at the C-28 position. The synthesized new 28-indole-betulin derivatives were evaluated for anticancer activity against seven human cancer lines (A549, MDA-MB-231, MCF-7, DLD-1, HT-29, A375, and C32). It was observed that MCF-7 breast cancer cells were most sensitive to the action of the 28-indole-betulin derivatives. The study shows that the lup-20(29)-ene-3-ol-28-yl 2-(1H-indol-3-yl)acetate caused the MCF-7 cells to arrest in the G1 phase, preventing the cells from entering the S phase. The performed cytometric analysis of DNA fragmentation indicates that the mechanism of EB355A action on the MCF-7 cell line is related to the induction of apoptosis. An in silico ADMET profile analysis of EB355A and EB365 showed that both compounds are bioactive molecules characterized by good intestinal absorption. In addition, the in silico studies indicate that the 28-indole-betulin derivatives are substances of relatively low toxicity.

7.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234741

RESUMO

Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Quinolinas , Antineoplásicos/química , Apoptose , Benzoquinonas , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Histonas , Humanos , Hidroxiquinolinas/farmacologia , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxigênio/metabolismo , Quinolinas/química , Quinonas/metabolismo , Quinonas/farmacologia , Estreptonigrina , Proteína Supressora de Tumor p53 , Proteína X Associada a bcl-2/metabolismo
8.
Biomolecules ; 12(10)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36291749

RESUMO

As part of the search for new medicinal substances with potential application in oncology, the synthesis of new compounds combining the betulin molecule and the indole system was carried out. The structure of the ester derivatives obtained in the Steglich reaction was confirmed by spectroscopic methods (1H and 13C NMR, HR-MS). The obtained new 3-indolyl betulin derivatives were evaluated for anticancer activity against several human cancer cell lines (melanomas, breast cancers, colorectal adenocarcinomas, lung cancer) as well as normal human fibroblasts. The significant reduction in MCF-7 cells viability for 28-hydroxy-(lup-20(29)-ene)-3-yl 2-(1H-indol-3-yl)acetate was observed at a concentration of 10 µg/mL (17 µM). In addition, cytometric analysis showed that this compound strongly reduces the proliferation rate of breast cancer cells. For this, the derivative showing the promising cytotoxic effect on MCF-7 breast cancer cells, the pharmacokinetic profile prediction was performed using in silico methods. Based on the results obtained in the study, it can be concluded that indole-functionalized triterpene EB367 is a promising starting point for further research in the field of breast cancer therapy or the synthesis of new derivatives.


Assuntos
Antineoplásicos , Neoplasias da Mama , Triterpenos , Humanos , Feminino , Linhagem Celular Tumoral , Nitrogênio , Triterpenos/farmacologia , Triterpenos/química , Antineoplásicos/química , Ésteres/farmacologia , Indóis/farmacologia , Proliferação de Células
9.
Int J Mol Sci ; 23(5)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35269667

RESUMO

Betulin and its derivatives, 28-propyne derivative EB5 and 29-diethyl phosphonate analog ECH147, are promising compounds in anti-tumor activity studies. However, their effect on kidney cells has not yet been studied. The study aimed to determine whether betulin and its derivatives-EB5 and ECH147-influence the viability and oxidative status of human renal proximal tubule epithelial cells (RPTECs). The total antioxidant capacity of cells (TEAC), lipid peroxidation product malondialdehyde (MDA) level, and activity of antioxidant enzymes (SOD, CAT, and GPX) were evaluated. Additionally, the mRNA level of genes encoding antioxidant enzymes was assessed. Cisplatin and 5-fluorouracil were used as reference substances. Betulin and its derivatives affected the viability and antioxidant systems of RPTECs. Betulin strongly reduced TEAC in a concentration-dependent manner. All tested compounds caused an increase in MDA levels. The activity of SOD, CAT, and GPX, and the mRNA profiles of genes encoding antioxidant enzymes depended on the tested compound and its concentration. Betulin showed an cisplatin-like effect, indicating its nephrotoxic potential. Betulin derivatives EB5 and ECH147 showed different impacts on the antioxidant system, which gives hope that these compounds will not cause severe consequences for the kidneys in vivo.


Assuntos
Antioxidantes , Cisplatino , Antioxidantes/farmacologia , Cisplatino/farmacologia , Células Epiteliais , Humanos , Peroxidação de Lipídeos , Estresse Oxidativo , RNA Mensageiro/genética , Superóxido Dismutase/genética , Triterpenos
10.
Pharmaceutics ; 15(1)2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36678664

RESUMO

Lipophilicity is one of the basic properties of a potential drug determining its solubility in non-polar solvents and, consequently, its ability to passively penetrate the cell membrane, as well as the occurrence of various pharmacokinetic processes, including adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Heterocyclic compounds containing a nitrogen atom play a significant role in the search for new drugs. In this study, lipophilicity as well as other physicochemical, pharmacokinetic and toxicity properties affecting the bioavailability of the quinolone-1,4-quinone hybrids are presented. Lipophilicity was determined experimentally as well as theoretically using various computer programs. The tested compounds showed low values of experimental lipophilicity and its relationship with the type of 1,4-quinone moiety. Introduction of the nitrogen atom reduced the lipophilicity depending on the position at the 5,8-quinolinedione moiety. The bioavailability of the tested compounds was determined in silico using the ADMET parameters. The obtained parameters showed that most of the hybrids can be used orally and do not exhibit neurotoxic effects. Similarity analysis was used to examine the relationship between the ADMET parameters and experimental lipophilicity. The ability of hybrids to interact with biological targets was characterized by global reactivity descriptors. The molecular docking study showed that the hybrids can inhibit the BCL-2 protein.

11.
Int J Mol Sci ; 24(1)2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36613643

RESUMO

Betulin, or naturally occurring triterpene, possesses promising antiproliferative activity. To further explore this potential, thirty-eight betulin acid ester derivatives modified at the C-28 position were tested for antitumor activities. Four human cancer cell lines, MV4-11 (leukemia), A549 (lung), PC-3 (prostate), MCF-7 (breast) as well as the normal BALB/3T3 (mouse fibroblasts) cell line were examined using MTT and SRB assays. A few derivatives exhibited strong antiproliferative activity with IC50 values between 2 and 5 µM. Subsequent mechanistic studies revealed that some derivatives induced apoptosis by inducing caspase-3/7 activity. A strong structure-activity correlation of tested compounds has been proposed along with experimental and in silico pharmacokinetic properties.


Assuntos
Antineoplásicos , Neoplasias , Triterpenos , Animais , Camundongos , Humanos , Linhagem Celular Tumoral , Ésteres/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Apoptose , Triterpenos/farmacologia , Caspases/metabolismo , Antineoplásicos/farmacologia , Proliferação de Células , Relação Estrutura-Atividade , Estrutura Molecular , Caspase 3/metabolismo
12.
Int J Mol Sci ; 22(22)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34830180

RESUMO

Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G2 phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Triterpenos/farmacologia , Acetileno/química , Antineoplásicos/farmacologia , Betula/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Estrutura Molecular , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Temozolomida/farmacologia , Triterpenos/síntese química , Triterpenos/química
13.
Sci Rep ; 11(1): 19984, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620981

RESUMO

The influence of the confinement on the changes of eating behaviors in men and women in Poland and between groups were assessed. Results were obtained for 112 men and 200 women. An anonymous questionnaire available on-line from 29 April to 19 May 2020 was the research tool. It contained questions about the frequency of consumption "before" and "during" confinement. Additionally, anthropometric measurements were declared by the respondents. An increase in the number of meals and an improvement in their regularity were observed in both groups. However, the frequency of snacking also increased. During lockdown women consumed potatoes, sweets, canned meat and eggs and men consumed canned meat more frequently. Products consumed less frequently were: fast food, instant soups and energy drinks (women), and white bread and fast food (men). The frequency of alcohol consumption also increased during lockdown. Average body weight and BMI increased significantly during social isolation. Body weight increase was declared by almost half of women and 40% of men. During the blockade period caused by the COVID-19 pandemic, changes in the dietary behavior of the study group of women and men were found. The nature of these changes varied according to gender and the dietary parameters analyzed.


Assuntos
COVID-19 , Comportamento Alimentar , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Índice de Massa Corporal , COVID-19/epidemiologia , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , Dieta , Feminino , Humanos , Masculino , Estado Nutricional , Distanciamento Físico , Polônia/epidemiologia , SARS-CoV-2/isolamento & purificação , Aumento de Peso
14.
Nutrients ; 13(6)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207087

RESUMO

Caffeine is the most common psychoactive substance available to adults, as well as to children and adolescents. The safety of its use in younger age groups requires further research. The aim of this study was to evaluate caffeine intake, to identify products and drinks that are the main sources of caffeine intake in the diet of the subjects and the risk of excessive caffeine intake with the diet of adolescents, stratified by gender. A cross-sectional study was conducted among 508 adolescents aged 16-18 years from southern Poland. Black tea, cola-based soft drinks and milk chocolate were the most frequently consumed products containing caffeine in the diet of the examined persons. The average caffeine intake was 95.54 mg/day (1.54 mg/kg b.w.). In 12.2% of the subjects the dose of 3 mg/kg b.w./day was exceeded, and in over 41.3% the dose causing sleep disorders was exceeded. The dose causing anxiety was also exceeded in 18.1% of the respondents, significantly more often in girls than boys (p = 0.0487).


Assuntos
Cafeína/análise , Café , Dieta , Ingestão de Alimentos , Adolescente , Bebidas/análise , Bebidas Gaseificadas/análise , Estudos Transversais , Feminino , Humanos , Masculino , Homens , Polônia , Medição de Risco , Chá/anatomia & histologia , Mulheres
15.
Pharmaceutics ; 13(6)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071116

RESUMO

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.

16.
Molecules ; 26(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572631

RESUMO

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 µM, and, for 7b, they were 0.76 and 0.8 µM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Fosfatos/química , Triterpenos/química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Humanos , Conformação Molecular
17.
Molecules ; 26(3)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503929

RESUMO

Betulin (BT) is a natural pentacyclic lupane-type triterpene exhibiting anticancer activity. Betulin derivatives bearing propynoyloxy and phosphate groups were prepared in an effort to improve the availability and efficacy of the drug. In this study, a comparative assessment of the in vitro anticancer activity of betulin and its four derivatives was carried out using two human breast cancer cell lines: SK-BR-3 and MCF-7. In both studied cell lines, 30-diethoxyphosphoryl-28-propynoylbetulin (compound 4) turned out to be the most powerful inhibitor of growth and inducer of cellular death. Detailed examination of that derivative pertained to the mechanisms underlying its anticancer action. Treatment with compound 4 decreased DNA synthesis and up-regulated p21WAF1/Cip1 mRNA and protein levels in both cell lines. On the other hand, that derivative caused a significant increase in cell death, as evidenced by increased lactate dehydrogenase (LDH) release and ethidium homodimer uptake. Shortly after the compound addition, an increased generation of reactive oxygen species and loss of mitochondrial membrane potential were detected. The activation of caspase-3 and fragmentation of genomic DNA suggested an apoptotic type of cell death. However, analysis of cellular morphology did not reveal any nuclear features typical of apoptosis. Despite necrosis-like morphology, dead cells exhibited activation of the cascade of caspases. These observations have led to the conclusion that compound 4 pushed cells to undergo a form of necrotic-like regulated cell demise.


Assuntos
Alcinos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Necrose/tratamento farmacológico , Fosfatos/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Bioorg Chem ; 106: 104478, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33272711

RESUMO

In this research, betulin derivatives were bonded to the 1,4-quinone fragment by triazole linker. Furthermore, the enzymatic assay used has shown that these compounds are a good DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. The anticancer activities of the hybrids were tested against a panel of human cell lines, like: melanoma, ovarian, breast, colon, and lung cancers. The structure-activity relationship showed that the activity depends on the type of 1,4-quinone moiety and the tumor cell lines used. It was also found that the anticancer effects were increasing against the cell line with higher NQO1 protein level, like: breast (T47D, MCF-7), colon (Caco-2), and lung (A549) cancers. The transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and apoptosis pathway (BCL-2 and BAX) for selected compounds were determined. The molecular docking study was carried out to examine the interaction between the hybrids and NQO1 enzyme. The computational simulation showed that the type of the 1,4-quinone moiety influences location of the compound in the active site of the enzyme. It is worth noting that the study of new hybrids of betulin as substrate for NQO1 protein may lead to new medical therapeutic applications in the future.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Quinonas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinonas/química , Relação Estrutura-Atividade , Especificidade por Substrato , Triterpenos/síntese química , Triterpenos/química
19.
Anticancer Res ; 40(11): 6151-6158, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33109552

RESUMO

BACKGROUND/AIM: Glioma is the most malignant tumour of the human brain still lacking effective treatment modalities. Betulin, a pentacyclic triterpene abundantly found in the birch bark, has been shown to demonstrate interesting anti-cancer activity towards many cancer cells. We determined the effects of acetylenic synthetic betulin derivatives (ASBDs) as anti-tumour agents on glioma cells in vitro. MATERIALS AND METHODS: T98G and C6 glioma cell viability and proliferation were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and BrdU (bromo deoxyuridine) test, respectively. Cell-cycle progression and induction of apoptosis were investigated with flow cytometry. RESULTS: ASBDs significantly decreased glioma cell viability/survival and inhibited proliferation in a dose-dependent manner in vitro. Moreover, ASBDs were more cytotoxic than clinically used chemotherapeutics - temozolomide and cisplatin. CONCLUSION: ASBDs may be considered for further study as potent anti-tumour agents in glioma treatment.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Triterpenos/farmacologia , Acetileno/química , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Humanos , Ratos , Temozolomida/farmacologia , Triterpenos/química
20.
Nutrients ; 12(10)2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33050404

RESUMO

Unexpected isolation, which has not yet been seen on a global scale, has created the conditions for evaluating nutrition in a situation of reduced spatial activity. The study aimed to assess the influence of lockdown on selected eating habits of Polish adults. An anonymous questionnaire was conducted, including questions about eating habits and self-reported anthropometric measurements, referring to "before" and "during" lockdown. We reported the findings of 312 adults (aged 41.12 ± 13.05 years). Overall, 64.1% of the participants were women, 77.7% urban inhabitants and 78.6% employed. The average length of social isolation was 50.79 ± 10.53 days. The majority (51.6%) of the respondents did not eat outside the house during lockdown (p < 0.0001). The number of meals eaten during the day during lockdown increased significantly, 11.2% of the respondents ate 5 and more meals (p < 0.0001). The percentage of people snacking between meals increased by 5.1% during lockdown (p = 0.0001). Eggs, potatoes, sweets, canned meat and alcohol were consumed considerably more commonly during lockdown, while fast-food products, instant soups and energy drinks were eaten or drunk significantly less frequently. A marked decrease in the number of daily servings of the following products was observed: bakery products, red meat, fast food, instant soups, sweet beverages and energy drinks. Conversely, the number of daily servings of sweets and canned meat significantly increased. Two thirds of the respondents reported body weight changes, with 45.86% of the participants being overweight during lockdown. Significant changes in the diet of Polish adults were found during lockdown due to COVID-19.


Assuntos
Infecções por Coronavirus , Dieta , Comportamento Alimentar , Comportamentos Relacionados com a Saúde , Pandemias , Pneumonia Viral , Isolamento Social , Aumento de Peso , Adulto , Betacoronavirus , Índice de Massa Corporal , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Fast Foods , Feminino , Preferências Alimentares , Humanos , Estilo de Vida , Masculino , Refeições , Pessoa de Meia-Idade , Obesidade/etiologia , Sobrepeso/etiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Polônia/epidemiologia , SARS-CoV-2 , Lanches , Inquéritos e Questionários , População Urbana
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