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1.
Article in English | WPRIM | ID: wpr-888781

ABSTRACT

In this study, three new germacranolide sesquiterpenes (1-3), together with six related known analogues (4-9) were isolated from the whole plant of Carpesium cernuum. Their structures were established by a combination of extensive NMR spectroscopic analysis, HR-ESIMS data, and ECD calculations. The anti-leukemia activities of all compounds towards three cell lines (HEL, KG-1a, and K562) were evaluated in vitro. Compounds 1-3 exhibited moderate cytotoxicity with IC


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Asteraceae/chemistry , Drug Screening Assays, Antitumor , Humans , K562 Cells , Phytochemicals/pharmacology , Sesquiterpenes, Germacrane/pharmacology
2.
Braz. j. med. biol. res ; 53(4): e8882, 2020. tab, graf
Article in English | LILACS | ID: biblio-1100927

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver worldwide. Liver resection and transplantation are currently the only effective treatments; however, recurrence and metastasis rates are still high. Previous studies have shown that the epithelial-mesenchymal transition (EMT) is a key step in HCC invasion and metastasis. Inhibition of EMT has become a new therapeutic strategy for tumors. Recently, puerarin, a well-characterized component of traditional Chinese medicine, has been isolated from Pueraria radix and exerts positive effects on many diseases, particularly cancers. In this study, CCK-8, EdU immunofluorescence, colony formation, wound healing, and migration assays were used to detect the effects of puerarin on HCC cells. We further analyzed the relationship between puerarin and miR-21/PTEN/EMT markers in HCC cell lines. Our results showed that HCC cell proliferation, migration, invasion, tumor formation, and metastasis were reduced by puerarin in vitro and in vivo. Additionally, puerarin inhibited the EMT process of HCC by affecting the expression of Slug and Snail. Moreover, oncogenic miR-21 was inhibited by puerarin, coupled with an increase in the tumor suppressor gene PTEN. Increasing miR-21 expression or decreasing PTEN expression reversed the inhibition effects of puerarin in HCC. These data confirmed that puerarin affects HCC through the miR-21/PTEN/EMT regulatory axis. Overall, puerarin may represent a chemopreventive and/or chemotherapeutic agent for HCC treatment.


Subject(s)
Animals , Male , Carcinoma, Hepatocellular/drug therapy , PTEN Phosphohydrolase/genetics , Epithelial-Mesenchymal Transition/drug effects , Isoflavones/therapeutic use , Liver Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Pyrroles , Drug Screening Assays, Antitumor , Carcinoma, Hepatocellular/genetics , MicroRNAs/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Disease Models, Animal , Isoflavones/pharmacology , Liver Neoplasms/genetics , Neoplasm Invasiveness , Antineoplastic Agents/pharmacology
3.
Rev. bras. cancerol ; 66(1)20200129.
Article in English | LILACS | ID: biblio-1049323

ABSTRACT

Introduction: Three vanadium complexes with orotic and glutamic acids, in their anion forms, were prepared and their in vitro cytotoxicity toward human lung fibroblasts (MRC-5), human hepatocellular carcinoma (HepG2) and human colorectal adenocarcinoma (Caco-2) are reported. Objective: Describe the synthesis and characterization of new vanadium complexes with orotic and glutamic acids, and test its antitumor activity against HepG2 and Caco-2. Method: The complexes were formulated as VO (oro), VO (α-glu) and VO (γ-glu) based on chemical, thermogravimetric analyses and infrared spectra. Results: Resazurin assay demonstrates its cytotoxicity against the HepG2 and Caco-2 cell lines with the IC50 ranging from 7.90 to 44.56 µmol.L-1. The cytotoxicity profiles indicate that the tumoral lines show more activity than the cells MRC-5, with selectivity indexes ranging from 1.58 to 8.96. Conclusion: The three complexes had better in vitro activity than cisplatin for both normal and cancer cell lines. The IC50 values are two to six times better for the cancer cell ines and five to seven times better for the normal cell lines. This study indicates that the complexes obtained are promising candidates for antitumor drugs.


Introdução: Foram preparados três complexos de vanádio com ácidos orótico e glutâmico, em suas formas aniônicas, e foi testada sua citotoxicidade in vitro para fibroblastos pulmonares humanos (MRC-5), carcinoma hepatocelular humano (HepG2) e adenocarcinoma colorretal humano (Caco-2). Objetivo: Descrever a síntese e caracterização de novos complexos de vanádio com ácidos orótico e glutâmico e testar sua atividade antitumoral contra HepG2 e Caco-2. Método: Os complexos foram formulados como VO (oro), VO (α-glu) e VO (γ-glu) com base em análises químicas, termogravimétricas e espectros no infravermelho. Resultados: O ensaio de resazurina demonstrou sua citotoxicidade contra as linhagens celulares HepG2 e Caco-2 com o IC50 variando de 7,90 a 44,56 µmol.L-1. Os perfis de citotoxicidade indicam que as linhas tumorais apresentam maior atividade que as células MRC-5, com índices de seletividade variando de 1,58 a 8,96. Conclusão: Os três complexos tiveram melhor atividade in vitro do que a cisplatina, tanto para linhagens celulares normais como cancerosas. Os valores de IC50 são de duas a seis vezes melhores para as linhagens celulares cancerosas e de cinco a sete vezes melhores para as linhagens celulares normais. Este estudo indica que os complexos obtidos são promissores candidatos a fármacos antitumorais.


Introducción: Tres complejos de vanadio con ácidos orótico y glutámico, en sus formas aniónicas, fueram preparados. Su citotoxicidad in vitro hacia los fibroblastos pulmonares humanos (MRC-5), el carcinoma hepatocelular humano (HepG2) y el adenocarcinoma colorrectal humano (Caco-2) son reportados. Objetivo: Los principales objetivos de este trabajo son describir la síntesis y caracterización de nuevos complejos de vanadio con ácidos orótico y glutámico y probar su actividad antitumoral contra el HepG2 y el Caco-2. Método: Los complejos fueron formulados como VO (oro), VO (α-glu) y VO (γ-glu) basados en análisis químicos, termogravimétricos y espectros infrarrojos. El ensayo de resazurina demuestra su citotoxicidad contra las líneas celulares HepG2 y Caco-2 con el IC50 que van de 7,90 a 44,56 µmol.L-1. Los perfiles de citotoxicidad indican que las líneas tumorales presentan mayor actividad que los MRC-5, con índices de selectividad que van de 1,58 a 8,96. Conclusión: Los tres complejos tuvieron mejor actividad in vitro que el cisplatino, tanto para líneas celulares normales como para líneas celulares cancerosas. Los valores del IC50 son de dos a seis veces mejores para las líneas celulares de cáncer y de cinco a siete veces mejores para las líneas celulares normales. Este estudio indica que los complejos obtenidos son candidatos prometedores para fármacos antitumorales.


Subject(s)
Humans , Orotic Acid/pharmacology , Vanadium Compounds/pharmacology , Glutamic Acid/pharmacology , Cell Line, Tumor/drug effects , In Vitro Techniques , Drug Screening Assays, Antitumor , Colorectal Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Carcinoma, Hepatocellular/drug therapy , Cancer-Associated Fibroblasts/drug effects , Lung Neoplasms/drug therapy , Antineoplastic Agents/pharmacology
4.
Article in English | WPRIM | ID: wpr-762686

ABSTRACT

PURPOSE: ATP-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy. This study was undertaken to assess the usefulness of ATP-CRA in advanced colorectal cancer (CRC) patients receiving adjuvant chemotherapy. METHODS: A total of 136 patients with curative resection between January 2006 and April 2014 were evaluated using ATP-CRA. Patients received either the FOLFOX or Mayo clinic regimen chemotherapy following assay results. The sensitive-group (S-group) was defined as a drug-producing ≥ 40% reduction in ATP, and the resistant-group (R-group) as an ATP reduction of < 40%. These 2 groups were further subdivided to produce 4 subgroups: the FOLFOX sensitive subgroup (the FS subgroup [n = 65]), the Mayo sensitive subgroup (the MS subgroup [n = 40]), the FOLFOX resistant subgroup (the FR subgroup [n = 10]), and the Mayo resistant subgroup (the MR subgroup [n = 21]). Clinical responses and survival results were compared for both treatment regimens. RESULTS: The FS and MS subgroups showed a better disease-free survival rate (29% vs. 40%, 35% vs. 47.6%) and overall survival rate (92.3% vs. 80.0%, 87.5% vs. 76.2%) than FR and MR subgroups. The FS and MS subgroups showed a longer time to relapse (20.2 months vs. 9.5 months, 17.6 months vs. 16.4 months) than the FR and MR subgroups. CONCLUSION: ATP-CRA tailored-chemotherapy has the potential to provide a survival benefit in resectable advanced CRC.


Subject(s)
Adenosine Triphosphate , Adenosine , Chemotherapy, Adjuvant , Colorectal Neoplasms , Disease-Free Survival , Drug Screening Assays, Antitumor , Drug Therapy , Humans , Recurrence , Survival Rate
5.
Article in Chinese | WPRIM | ID: wpr-773230

ABSTRACT

According to drug design flattening principle,a series of novel indole podophyllotoxin derivatives which were introduced different indole substituents in C-4 position on the basis of podophyllotoxin nucleus were synthesized with the starting material podophyllotoxin and 1 H-indole-5-carboxylic acid. Its anti-tumor activity in vitro was tested in order to screen for high-efficiency and low-toxic compounds. Six target compounds were synthesized,and were confirmed by~1 H-NMR,~(13)C-NMR,HR-ESI-MS and melting point determination analysis. All these target compounds were not reported by previous literature. Using etoposide as positive control drug,all the target compounds were screened for cytotoxicity against He La cells,K562 cells and K562/A02 cell in vitro by MTT method. The antitumor activity screening results showed that compounds 4 b,4 e,4 f exhibited higher inhibitory rate against He La cells and K562 cells than those of control drug VP-16. This route has the advantages on simple operation and reasonable design,provides some practical reference value for the further development on the structure modification of podophyllotoxin and study on anti-tumor activity.


Subject(s)
Antineoplastic Agents , Pharmacology , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Indoles , Pharmacology , K562 Cells , Podophyllotoxin , Pharmacology , Structure-Activity Relationship
6.
Article in English | WPRIM | ID: wpr-776897

ABSTRACT

Romipeptides A and B (1 and 2), two new romidepsin derivatives, and three known compounds, chromopeptide A (3), romidepsin (4) and valine-leucine dipeptide (5) were isolated from the fermentation broth of Chromobacterium violaceum No. 968. Their structures were elucidated by interpretation of their UV, HR-ESI-MS and NMR spectra. The absolute configuration of compound 1 and 2 were established by single crystal X-ray diffraction analysis. Compounds 1-5 were evaluated for their anti-proliferative activities against three human cancer cell lines, SW620, HL60, and A549. The results showed most of these compounds exhibited antitumor activities in vitro, in which compound 2 displayed potent cytotoxicity to SW620, HL60 and A549 cell lines, with IC of 12.5, 6.7 and 5.7 nmol·L, respectively.


Subject(s)
Antineoplastic Agents , Chemistry , Pharmacology , Cell Line, Tumor , Cell Proliferation , Cell Survival , Chemistry Techniques, Analytical , Chromobacterium , Metabolism , Depsipeptides , Chemistry , Pharmacology , Dipeptides , Chemistry , Drug Screening Assays, Antitumor , Fermentation , Humans , Molecular Structure , Peptides, Cyclic , Chemistry
7.
Article in English | WPRIM | ID: wpr-776884

ABSTRACT

Eight new annonaceous acetogenins, squamotin A-D (1-4), annosquatin IV-V (5 and 6), muricin O (7) and squamosten B (8), together with four known ones (9-12) were isolated from the seeds of Annona squamosa. Their structures were elucidated by chemical methods and spectral data. The inhibitory activities of compound 1-9 against three multidrug resistance cell lines were evaluated. All tested compounds showed strong cytotoxicity.


Subject(s)
Acetogenins , Chemistry , Pharmacology , Toxicity , Annona , Chemistry , Antineoplastic Agents, Phytogenic , Chemistry , Pharmacology , Toxicity , Cell Line, Tumor , Cell Survival , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Plant Extracts , Chemistry , Pharmacology , Toxicity , Seeds , Chemistry
8.
São Paulo; s.n; s.n; 2019. 132 p. graf, tab.
Thesis in English | LILACS | ID: biblio-999486

ABSTRACT

Miltefosine (hexadecylphosphocholine, HePC), a synthetic antitumor designed from natural phospholipids, is clinically approved for cutaneous metastases of breast cancer and cutaneous lymphoma. This drug acts mainly at cellular membrane level, where it accumulates and interferes with lipid metabolism and lipid-dependent signaling pathways leading the cells to apoptosis. However, HePC systemic and peroral administration induces hemolysis and mucosal toxicity, respectively. To overcome these limitations, we investigated the protective properties of colloidal polymeric micelles (PM) composed by Pluronics, triblock copolymers of poly(ethylene oxide) and poly(propylene oxide). We found that both Pluronic composition and concentration modulate the hemolytic profile of incorporated drug (HePC-PM) by increasing the drug amount to cause in vitro hemolysis. Moreover, small-angle X-ray scattering (SAXS) was used to assess structural information of interactions between HePC and PM. Additionally, we showed that HePC-PM prevented mucosal irritation, decreasing bleeding and lysis of blood vessels in a chicken chorioallantoic membrane model. Interestingly, HePC-PM increased the in vitro selective cytotoxicity against cervix tumor cells rather healthy fibroblasts, suggesting a differential uptake of these nanostructures by tumor cells. Furthermore, we also found that HePC induces cytotoxicity and decrease cell survival, migration and proliferation in osteosarcoma cells in vitro. We showed that cytotoxicity by HePC is associated with caspase-3 activation, DNA fragmentation, apoptotic-like bodys formation and inhibition of both constitutive and cytokine-stimulated Akt/PKB phosphorylation. HePC-PM clearly reduces the drug cytotoxic effects. Finally, we demonstrated that Pluronic F127 polymeric micelles are efficient for cargo delivering the encapsulated drug preferentially into tumor cells rather than healthy cells. These findings together suggest that Pluronic F127 PM reduce drug side effects and provide a potential alternative for systemic delivery of HePC, as well as other amphiphilic drugs


Miltefosina (hexadecilfosfocolina, HePC), um fármaco antitumoral sintético desenvolvido a partir de fosfolipídios naturais, é clinicamente aprovada para o tratamento tópico de metástases de câncer de mama e linfomas cutâneos. Atua principalmente nas membranas celulares, onde se acumula e interfere no metabolismo lipídico e nas vias de sinalização dependentes de lipídios levando as células à apoptose. No entanto, quando administrada sistemicamente ou oralmente a HePC induz hemólise e toxicidade de mucosas, respectivamente. Para superar estas reações adversas investigamos os efeitos protetores conferidos por micelas poliméricas coloidais (PM) compostas por Pluronics, copolímeros tribloco de poli(óxido de etileno) e poli(óxido de propileno). Inicialmente, encontramos que a composição e concentração do Pluronic modulam o perfil hemolítico do fármaco encapsulado (HePC-PM), aumentando a quantidade necessária de HePC para causar hemólise in vitro. Além disso, utilizamos o espalhamento de raios-X a baixo ângulo (SAXS) para obter informações estruturais das interações entre HePC e PM. Em seguida, mostramos que HePC-PM preveniu a irritação da mucosa, diminuindo a hemorragia e a vasoconstricção em membrana corioalantóica de ovos embrionados. Estudos in vitro demonstraram que a HePC-PM aumentou seletivamente a citotoxicidade contra células de carcinoma HeLa em relação a fibroblastos saudáveis, sugerindo captação diferencial dessas nanoestruturas pelas células tumorais. Além disso, relatamos que, in vitro, a HePC induz citotoxicidade, diminui a sobrevivência, migração e proliferação osteossarcomas. Esta citotoxicidade está associada à ativação da caspase-3, fragmentação do DNA, formação de corpos apoptóticos e inibição da fosforilação de Akt/PKB. Adicionalmente, HePC-PM reduz os efeitos citotóxicos nestas linhagens. Finalmente, demonstramos que as micelas poliméricas de Pluronic F127 são eficientes para a entrega intracelular fármacos preferencialmente em células tumorais, e em menor grau em células saudáveis. Em conjunto, os dados sugerem que este sistema nanoestruturado reduz a toxicidade da HePC e representa uma alternativa potencial para a administração sistêmica deste e de outros fármacos anfifílicos


Subject(s)
Drug Screening Assays, Antitumor , Pharmaceutical Preparations/administration & dosage , Poloxamer/analysis , Nanostructures , Poloxamer/therapeutic use , Drug Therapy, Combination , Neoplasms/physiopathology
9.
Braz. J. Pharm. Sci. (Online) ; 55: e18204, 2019. tab, graf
Article in English | LILACS | ID: biblio-1039079

ABSTRACT

The development and clinical application of 2-methoxyestradiol (2-ME) as a new type of antitumor drug are limited due to its poor solubility, rapid metabolism in vivo, and large oral dosage. 2-ME-loaded pH-sensitive liposomes (2-ME-PSLs) was prepared containing the lipids, Lipoid E-80 (E-80), cholesteryl hemisuccinate (CHEMS), and cholesterol (CHOL) via thin-film ultrasonic dispersion. First, preparation conditions of 2-ME-PSLs were optimized by orthogonal test. Then 2-ME-PSL was characterized, and the release behavior and stability of 2-ME-PSL in vitro were evaluated. The optimal preparation conditions for 2-ME-PSLs were as follows: 2-ME : E-80+CHEMS 1:15; CHOL : E-80+CHEMS 1:5; ultrasonication time 20 minutes. The mean particle size, PDI, zeta potential, and entrapment efficiency (EE) of 2-ME-PSLs were 116 ± 9 nm, 0.161 ± 0.025, −22.4 ± 1.7 mV, and 98.6 ± 0.5%, respectively. As viewed under a transmission electron microscope, 2-ME-PSLs were well dispersed and almost spherical. They exhibited significant pH-sensitive properties and were fairly stable when diluted with a physiological solution. In conclusion, 2-ME-PSLs were successfully prepared and possessed a favorable pH sensitivity and good dissolution stability with a normal solution


Subject(s)
In Vitro Techniques/instrumentation , /pharmacokinetics , Liposomes/analysis , Drug Screening Assays, Antitumor/classification , Hydrogen-Ion Concentration/drug effects
10.
São Paulo; s.n; s.n; 2019. 136 p. graf, tab, ilus.
Thesis in Portuguese | LILACS | ID: biblio-995079

ABSTRACT

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados


Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados


Subject(s)
Animals , Male , Mice , Drug Screening Assays, Antitumor , Nanoparticles/metabolism , Antimetabolites, Antineoplastic/classification , Nanotechnology/classification , Lung Neoplasms/physiopathology
11.
Protein & Cell ; (12): 770-784, 2018.
Article in English | WPRIM | ID: wpr-757993

ABSTRACT

Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor-kappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.


Subject(s)
Antineoplastic Agents , Pharmacology , Therapeutic Uses , Apoptosis , Bortezomib , Pharmacology , Therapeutic Uses , Cell Cycle , Cell Proliferation , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Multiple Myeloma , Drug Therapy , Metabolism , Pathology , NF-kappa B , Metabolism , Signal Transduction , Structure-Activity Relationship , Ubiquitin-Protein Ligases , Genetics , Metabolism
12.
Article in English | WPRIM | ID: wpr-812385

ABSTRACT

Nine new ent-kaurane diterpenoids, named scopariusols L-T (1-9), were isolated from the aerial parts of Isodon scoparius. Their structures were characterized mainly by analyzing the NMR and HR-ESI-MS data, and the absolute configuration of 1 was determined by single-crystal X-ray diffraction. Compound 1 was active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and it also inhibited NO production in LPS-stimulated RAW264.7 cells, with an IC value of 0.6 μmol·L.


Subject(s)
Animals , Antineoplastic Agents, Phytogenic , Chemistry , Pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Diterpenes, Kaurane , Chemistry , Pharmacology , Drug Screening Assays, Antitumor , Drugs, Chinese Herbal , Chemistry , Pharmacology , HL-60 Cells , Humans , Isodon , Chemistry , Lipopolysaccharides , Pharmacology , Macrophages , Mice , Molecular Structure , Nitric Oxide , Nuclear Magnetic Resonance, Biomolecular , Plant Components, Aerial , Chemistry
13.
Article in English | WPRIM | ID: wpr-812350

ABSTRACT

A series of new hybrids of dehydroandrographolide (TAD), a biologically active natural product, bearing nitric oxide (NO)-releasing moieties were synthesized and designated as NO-donor dehydroandrographolide. The biological activities of target compounds were studied in human erythroleukemia K562 cells and breast cancer MCF-7 cells. Biological evaluation indicated that the most active compound I-5 produced high levels of NO and inhibited the proliferation of K562 (IC 1.55 μmol·L) and MCF-7 (IC 2.91 μmol·L) cells, which were more potent than the lead compound TAD and attenuated by an NO scavenger. In conclusion, I-5 is a novel hybrid with potent antitumor activity and may become a promising candidate for future intensive study.


Subject(s)
Antineoplastic Agents , Chemistry , Cell Proliferation , Diterpenes , Chemistry , Pharmacology , Drug Design , Drug Screening Assays, Antitumor , Humans , K562 Cells , MCF-7 Cells , Nitric Oxide , Chemistry , Pharmacology , Structure-Activity Relationship
14.
Article in English | WPRIM | ID: wpr-773596

ABSTRACT

Nine new ent-kaurane diterpenoids, named scopariusols L-T (1-9), were isolated from the aerial parts of Isodon scoparius. Their structures were characterized mainly by analyzing the NMR and HR-ESI-MS data, and the absolute configuration of 1 was determined by single-crystal X-ray diffraction. Compound 1 was active against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), and it also inhibited NO production in LPS-stimulated RAW264.7 cells, with an IC value of 0.6 μmol·L.


Subject(s)
Animals , Antineoplastic Agents, Phytogenic , Chemistry , Pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Diterpenes, Kaurane , Chemistry , Pharmacology , Drug Screening Assays, Antitumor , Drugs, Chinese Herbal , Chemistry , Pharmacology , HL-60 Cells , Humans , Isodon , Chemistry , Lipopolysaccharides , Pharmacology , Macrophages , Mice , Molecular Structure , Nitric Oxide , Nuclear Magnetic Resonance, Biomolecular , Plant Components, Aerial , Chemistry
15.
Article in English | WPRIM | ID: wpr-773561

ABSTRACT

A series of new hybrids of dehydroandrographolide (TAD), a biologically active natural product, bearing nitric oxide (NO)-releasing moieties were synthesized and designated as NO-donor dehydroandrographolide. The biological activities of target compounds were studied in human erythroleukemia K562 cells and breast cancer MCF-7 cells. Biological evaluation indicated that the most active compound I-5 produced high levels of NO and inhibited the proliferation of K562 (IC 1.55 μmol·L) and MCF-7 (IC 2.91 μmol·L) cells, which were more potent than the lead compound TAD and attenuated by an NO scavenger. In conclusion, I-5 is a novel hybrid with potent antitumor activity and may become a promising candidate for future intensive study.


Subject(s)
Antineoplastic Agents , Chemistry , Cell Proliferation , Diterpenes , Chemistry , Pharmacology , Drug Design , Drug Screening Assays, Antitumor , Humans , K562 Cells , MCF-7 Cells , Nitric Oxide , Chemistry , Pharmacology , Structure-Activity Relationship
16.
São Paulo; s.n; s.n; 2018. 139 p. tab, graf, ilus.
Thesis in Portuguese | LILACS | ID: biblio-997679

ABSTRACT

As neoplasias malignas, doenças mundialmente conhecidas como câncer, possuem um dos tratamentos mais onerosos, tóxicos e de baixa seletividade na terapêutica atual. Adicionalmente, o contínuo crescimento da incidência da doença também representa em uma grande problemática. Os produtos de origem natural se apresentam como alternativas para o tratamento de diversas doenças, incluindo o câncer. A capsaicina, produto natural proveniente das pimentas do gênero Capsicum, apresenta propriedades antineoplásicas, portanto, pode ser utilizada como protótipo para obtenção de análogos. Quatro séries foram planejadas e sintetizadas, obtendo-se compostos ureídicos e tioureídicos. A estratégia sintética se baseou na reação da piperonilamina ou vanililamina com isocianatos ou isotiocianatos, ligados a substituintes aromáticos ou alquílicos. Vinte e sete análogos foram sintetizados com rendimentos variando entre 22 a 90 %. Todos os compostos apresentaram aspecto sólido variando a cor de branco a levemente amarelados. Para a caracterização das substâncias obtidas foram utilizados dados de RMN 1H e 13C, ponto de fusão e a determinação de pureza foi realizada mediante HPLC. Todos os compostos foram submetidos a ensaios de avaliação da atividade citotóxica por redução do MTT contra linhagens de células cancerígenas e células sadias. Os compostos RPF652, RPF 512 - 514) apresentaram atividade comparável ou superior ao protótipo com valores de IC50 na faixa de micromolar. Os resultados apontados pela modelagem molecular indicam que descritores eletrônicos como Ehomo e Elumo podem estar associados à atividade do composto, ClogP (3,92) pode favorecer melhor permeabilidade na membrana celular, e o maior número de sítios de acepção de ligação de hidrogênio podem corroborar com a citotoxidade em linhagem A2058. Particularmente, o análogo RPF652 apresentou atividade pronunciada com valores de IC50 de 55, 67, e 87 µM contra as células A2058, SK-MEL 25, e U87, respectivamente, o que representa atividade de superior à capsaicina. Como uma tendência o composto RPF652 causou parada no ciclo de linhagem B-RAF B16F10 não levando a célula à morte. Porém esta linhagem não apresenta mutação no códon V600E. Em contraponto, o análogo RPF652 apresentou maior potência contra linhagem V600EB-RAF A2058 mutada, indicando possível seletividade em linhagens que apresentam a mutação no códon V600E da proteína B-RAF. Ademais, novos esforços devem ser concentrados no análogo RPF652 para melhor elucidação mecanística de sua atividade


Malignant neoplasms have one of the most expensive, non-selective and toxic treatment of present times. This situation, combined with the rising incidence rate, represents a major problem for humanity. The use of natural products can be an alternative for treatment of several diseases, including cancer. Capsaicin is a natural product derived from Capsicum peppers, with reported anticancer activity and can be used as prototype for the design of new molecules with remarkable activity. Capsaicin analogues were designed and synthesized in four series of derivatives, replacing the prototype amide bond with urea and thiourea functions. The synthetic approach builds the urea/ thiourea scaffold using the reaction of piperonyl/ vanilyl amine with alkyl and aryl isocyanides/ isothiocyanides. Twenty-seven new compounds were obtained with yields from 22 to 90 %, and were fully characterized using 1H and 13C NMR, the purity was determined by melting point and HPLC. All of the obtained compounds were evaluated in MTT cytotoxic assays against different cancer cell-lines (B16F10, A2058, SK-MEL 25 and U-87), and compared with healthy human cells (T75). Additionally, the most active compound was submitted to a cell cycle arrest assay. The thiourea derivative RPF652 was the most active compound, and the urea derivatives RPF512, RPF513 and RPF514 showed good micromolar IC50 values. This results, when correlated with several in silico-calculated properties for the obtained molecules, suggests that ClogP, Ehomo, Elumo and the number of hydrogen-bond acception sites may be correlated to the anticancer activity reported. RPF652 especially, showed IC50 values with superior activity and better selectivity index when compared with capsaicin. The cell-cycle assay of RPF652 showed significant arrest in V600E-codon B-RAF non-mutated cell lines (B16F10) without killing it. V600E-codon B-RAF mutated cells A2058, were significantly more sensitive to the compound. These findings may suggest some insights about the mechanism of action and targets of this compounds


Subject(s)
Drug Screening Assays, Antitumor , Capsaicin/analysis , Antineoplastic Agents/classification , Capsicum/classification , Chemistry, Pharmaceutical/instrumentation , Genus Pimenta/adverse effects , Neoplasms/drug therapy
17.
São Paulo; s.n; s.n; 2018. 79 p. tab, ilus, graf.
Thesis in Portuguese | LILACS | ID: biblio-909540

ABSTRACT

O carcinoma hepatocelular (HCC) é o sexto mais frequente e a segunda maior causa de mortalidade por câncer no mundo, além de apresentar alta taxa de recidiva. A associação de sorafenibe (SO) com agentes quimiopreventivos representa uma estratégia importante para aumentar a eficácia do tratamento e minimizar a reincidência da doença. Em estudos anteriores demonstrou-se o potencial quimiopreventivo da tributirina (TB), pró-fármaco do ácido butírico (AB), em modelo de hepatocarcinogênese experimental. A atividade da TB tem sido relacionada à inibição do desenvolvimento de lesões préneoplásicas, bem como à indução de apoptose. Assim, o presente estudo teve como objetivo avaliar a ação anticarcinogênica da TB e do SO, isoladamente ou em associação no HCC. Nesse sentido, implantes singênicos foram realizados no flanco de ratos Fischer- 344 a partir de células da linhagem neoplásica JM-1. Os animais foram distribuídos nos seguintes grupos: Grupo controle isocalórico [CO; Maltodextrina (300 mg/100 g p.c.) e solução veículo (solução de etanol a 12.5% e Cremofor a 12.5% em água estéril)]; Grupo TB (200 mg/100 g p.c. e solução veículo); Grupo SO [Maltodextrina (300 mg/100 g p.c. tosilato de SO (3 mg/100 g p.c.) em solução veículo] e Grupo associação [AS; TB (200 mg/100 g p.c) e tosilato de SO (3 mg/100 g p.c.) em solução veículo]. Os implantes de células JM-1 originaram neoplasias com características pouco diferenciadas. Os tratamentos com SO e AS retardaram (p<0,05) o desenvolvimento das neoplasias, além de reduzirem (p<0,05) suas massa e aumentem (p<0,05) a sobrevida em relação ao grupo CO. Não houve diferença na porcentagem de área necrótica das neoplasias entre os tratamentos. Porém, foi observada uma correlação negativa (p<0,05) entre o tamanho da neoplasia e a área necrótica, sendo que quanto menor a área da neoplasia maior a extensão da necrose, independente do tratamento. Foi observado aumento (p<0,05) das concentrações hepáticas de AB nos grupos TB, SO e AS. Já na neoplasia, apenas os grupos TB e SO demonstraram aumento (p<0,05) na concentração de AB. Além disso, os tratamentos com SO e AS aumentaram (p<0,05) a concentração tecidual de SO na neoplasia em relação ao CO. Nesse sentido, foi observado que grupo AS apresentou 5 vezes mais SO na neoplasia quando comparado ao grupo SO. Os tratamentos com TB e SO isoladamente ou em associação reduziram (p<0,05) a expressão de CK19 em relação ao grupo CO. Em relação à avaliação da proliferação celular, os grupos TB, SO e AS apresentaram redução (p<0,05) do índice de proliferação celular quando comparados ao grupo CO. Foi observado por meio da análise imunoistoquímica para pERK, que os animais tratados com SO e AS reduziram (p<0,05) as áreas positivas quando comparadas às dos animais do grupo CO. Além disso, também foi observada por meio de marcação imunoistoquímica uma redução (p<0,05) nas áreas positivas para CK8 nos grupos SO e AS quando comparadas às do grupo CO. Em relação à caspase-3 clivada, foi observado por imunoistoquímica que o tratamento com TB aumentou (p<0,05) o índice de células positivas para caspase-3 clivada quando comparado ao CO. Esse dado foi comprovado pela análise de western blot. Foi observado por meio da análise imunoistoquímica para H3K9, um aumento (p<0,05) da acetilação no grupo TB quando comparado ao grupo CO. Em relação à expressão em nível proteico de pAKT, foi observado por meio da análise imunoistoquímica uma redução (p<0,05) no grupo TB em comparação ao grupo CO. O presente estudo demonstrou que os implantes de células JM-1 no flanco de ratos Fischer-344 originaram neoplasias com características que lembram a organização hepatocítica de um HCC convencional. O tratamento com TB foi capaz de reduzir a proliferação celular e induzir apoptose. Os tratamentos com SO e com a AS foram capazes de retardar o desenvolvimento, aumentar a sobrevida, reduzir a massa das neoplasias, induzirem diferenciação celular e reduzirem a proliferação celular, melhorando o prognóstico da doença. Os tratamentos com SO e AS apresentaram atividade quimioterápica semelhante. No entanto, a coadministração de SO e TB foi capaz de aumentar a biodisponibilidade do SO para a neoplasia


Hepatocellular carcinoma (HCC) is the sixth most frequent and the second largest cause of cancer mortality in the world, besides presenting a high rate of recurrence. The association of sorafenib (SO) with chemopreventive agents represents an important strategy to increase the efficacy of the treatment and to minimize recurrence of the disease. In previous studies the chemopreventive potential of tributyrin (TB), a butyric acid prodrug (AB), was demonstrated in a model of experimental hepatocarcinogenesis. TB activity has been linked to inhibition of the development of pre-neoplastic lesions as well as to the induction of apoptosis. Thus, the present study aimed to evaluate the anticarcinogenic action of TB and SO, either alone or in combination in HCC. In this sense, syngeneic implants were performed on the flank of Fischer-344 rats from cells of the JM-1 neoplastic lineage. The animals were divided into the following groups: Control group [CO; Maltodextrin (300 mg / 100g p.c.) and carrier solution (12.5% ethanol solution and 12.5% Cremophor in sterile water)]; TB group (200 mg / 100 g p.c. and carrier solution); Group SO [Maltodextrin (300 mg / 100 g pc tosylate of SO (3 mg / 100 g pc) in vehicle solution] and Association group [AS; TB (200 mg / 100 g pc) and SO tosylate (3 mg / 100 (p <0.05), the development of the neoplasms, as well as the reduction (p <0.05), and the survival rate was higher (p <0.05) than the CO group. There was no difference in the percentage of necrotic area of the neoplasms between the treatments. (p <0.05) of the hepatic AB concentrations in the TB, SO and AS groups, although the size of the neoplasia and the necrotic area were higher. In the neoplasia, only the TB and SO groups showed an increase (p <0.05) in AB concentration. In addition, treatments with SO and AS increased (p <0.05) the tissue concentration of SO in the neoplasia in relation to CO. In this sense, it was observed that AS group presented 5 times more SO in the neoplasia when compared to the SO group. Treatments with TB and SO alone or in combination reduced (p <0.05) the expression of CK19 in relation to the CO group. In relation to the evaluation of cell proliferation, the TB, SO and AS groups presented a reduction (p <0.05) in the cell proliferation index when compared to the CO group. It was observed by the immunohistochemical analysis for pERK that the animals treated with SO and AS reduced (p <0.05) the positive areas when compared to the animals of the CO group. In addition, a reduction (p <0.05) in the CK8 positive areas in the SO and AS groups when compared to the CO groups was also observed by immunohistochemical labeling. In relation to the cleaved caspase-3, it was observed by immunohistochemistry that the TB treatment increased (p <0.05) the index of caspase-3 positive cells cleaved when compared to CO. This was confirmed by western blot analysis. It was observed by immunohistochemical analysis for H3K9, an increase (p <0.05) in the acetylation of the TB group when compared to the CO group. Regarding the protein level expression of pAKT, a reduction (p <0.05) in the TB group was observed through the immunohistochemical analysis when compared to the CO group. The present study demonstrated that JM-1 cell implants in the flank of Fischer-344 mice originated neoplasms with features reminiscent of the hepatocyte organization of a conventional HCC. TB treatment was able to reduce cell proliferation and induce apoptosis. SO and AS treatments were able to delay the development, increase survival, reduce the mass of neoplasms, induce cell differentiation and reduce cell proliferation, improving the prognosis of the disease. SO and AS treatments showed similar chemotherapy activity. However, co-administration of SO and TB was able to increase the bioavailability of SO to the neolasia


Subject(s)
Animals , Male , Female , Rats , Drug Therapy , Pharmaceutical Preparations/analysis , Carcinoma, Hepatocellular/drug therapy , Drug Screening Assays, Antitumor , Drug Therapy, Combination
18.
An. acad. bras. ciênc ; 89(3): 1369-1379, July-Sept. 2017. tab, graf
Article in English | LILACS | ID: biblio-886755

ABSTRACT

ABSTRACT Natural steroids and triterpenes such as b-sitosterol, stigmasterol, lupeol, ursolic and betulinic acids were transformed into its hexanoic and oleic esters, to evaluate the influence of chemical modification towards the cytotoxic activities against tumor cells. The derivatives were evaluated against five tumor cell lines [OVCAR-8 (ovarian carcinoma); SF-295 (glioblastoma); HCT-116 (colon adenocarcinoma); HL-60 (leukemia); and PC-3 (prostate carcinoma)] and the results showed only betulinic acid hexyl ester exhibits cytotoxic potential activity.


Subject(s)
Humans , Triterpenes/pharmacology , Lamiaceae/chemistry , Pentacyclic Triterpenes/pharmacology , Fabaceae/chemistry , Antineoplastic Agents/pharmacology , Triterpenes/isolation & purification , Triterpenes/chemistry , Drug Screening Assays, Antitumor , Lamiaceae/classification , Inhibitory Concentration 50 , Cell Line, Tumor , Esters , Pentacyclic Triterpenes/isolation & purification , Pentacyclic Triterpenes/chemistry , Fabaceae/classification , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/chemistry
19.
Medisan ; 21(3)mar. 2017. tab, ilus
Article in Spanish | LILACS | ID: biblio-841674

ABSTRACT

Se realizó un estudio descriptivo y retrospectivo sobre la conducción de ensayos clínicos durante 23 años en Santiago de Cuba, con el objetivo de describir la aplicación de 3 productos inmunoterapéuticos (CIMAher-Nimotuzumab, CIMAvax-EGF y Vaxira-Racotumomab) para el tratamiento de pacientes con cáncer en hospitales y policlínicos de la provincia. Se revisaron los informes finales de dichos ensayos, así como la información disponible del centro promotor desde 1992 hasta 2015. Se ejecutaron 20 protocolos de ensayos clínicos por 500 investigadores de 25 especialidades, distribuidos en 4 hospitales de la provincia y 2 se extendieron a 4 áreas de atención primaria de salud. Se concluyó que la aplicación de estos productos inmunoterapéuticos contribuyó al registro sanitario de estos, lo cual enriqueció el arsenal terapéutico para los afectados por cáncer en Santiago de Cuba, con un elevado impacto social


A retrospective descriptive study on the presentation of clinical trials was carried out during 23 years in Santiago de Cuba, with the objective of describing the implementation of 3 immunotherapeutical products (CIMAher-Nimotuzumab, CIMAvax-EGF and Vaxira-Racotumomab) for the treatment of patients with cancer in hospitals and polyclinics from the province. The final reports of each clinical trial and the available information of the promoter center were reviewed from 1992 to 2015. Twenty protocols of clinical trials were implemented by 500 investigators of 25 specialties distributed in 4 hospitals of the province and 4 primary health care areas, where 2 clinical trials in patients with lung cancer were carried out. It was concluded that the implementation of these immunotherapeutical products contributed to the health registration of them, enriching the therapeutic arsenal for the treatment of patients with cancer in Santiago de Cuba, with a high social impact


Subject(s)
Humans , Male , Female , Immunoassay , Drug Screening Assays, Antitumor , Immunotherapy , Neoplasms/therapy , Medical Oncology
20.
Article in English | WPRIM | ID: wpr-812114

ABSTRACT

The present study was designed to perform structural modifications of of neobavaisoflavone (NBIF), using an in vitro enzymatic glycosylation reaction, in order to improve its water-solubility. Two novel glucosides of NBIF were obtained from an enzymatic glycosylation by UDP-glycosyltransferase. The glycosylated products were elucidated by LC-MS, HR-ESI-MS, and NMR analysis. The HPLC peaks were integrated and the concentrations in sample solutions were calculated. The MTT assay was used to detect the cytotoxic activity of compounds in cancer cell lines. Based on the spectroscopic analyses, the two novel glucosides were identified as neobavaisoflavone-4'-O-β-D-glucopyranoside (1) and neobavaisoflavone-4', 7-di-O-β-D-glucopyranoside (2). Additionally, the water-solubilities of compounds 1 and 2 were approximately 175.1- and 4 031.9-fold higher than that of the substrate, respectively. Among the test compounds, only NBIF exhibited weak cytotoxicity against four human cancer cell lines, with IC values ranging from 63.47 to 72.81 µmol·L. These results suggest that in vitro enzymatic glycosylation is a powerful approach to structural modification, improving water-solubility.


Subject(s)
Antineoplastic Agents , Metabolism , Pharmacology , Bacillus , Cell Line, Tumor , Colorimetry , Drug Screening Assays, Antitumor , Glucosides , Chemistry , Glycosyltransferases , Metabolism , Humans , Isoflavones , Chemistry , Molecular Structure , Solubility
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