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1.
Bioorg Chem ; 150: 107600, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38945086

RESUMO

In this study, we investigated how the replacement of the tetrahydrothiophene ring of biotin with either an oxolane or (methyl)pyrrolidine moiety may affect its molecular interactions, in an effort to identify alternative affinity ligands suitable for in vitro and in vivo applications in synthetic biology. Initial molecular dynamics (MD) simulations suggested the potential formation of a hydrogen bond between either the oxygen or nitrogen atom of the envisaged tetrahydroheteryl analogues and the Thr90 residue of streptavidin, mirroring the sulfur-centered hydrogen bond detected by the crystallographic analysis of the biotin-streptavidin interaction. Therefore, oxy-, aza-, and N-methylazabiotin were readily synthesized starting from chiral five- or six-carbon sugar precursors. Based on fluorescence-based titration experiments using the corresponding fluorescein conjugates, oxybiotin showed a binding behavior similar to biotin with streptavidin, while both amino analogues displayed lower binding capacities. Notably, azabiotin exhibited a pH-dependent interaction profile, demonstrating enhanced binding under acidic conditions but weaker binding under basic pH, which could be exploited for various purposes.

2.
Molecules ; 27(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35956789

RESUMO

The targeted quantitative NMR (qNMR) approach is a powerful analytical tool, which can be applied to classify and/or determine the authenticity of honey samples. In our study, this technique was used to determine the chemical profiles of different types of Polish honey samples, featured by variable contents of main sugars, free amino acids, and 5-(hydroxymethyl)furfural. One-way analysis of variance (ANOVA) was performed on concentrations of selected compounds to determine significant differences in their levels between all types of honey. For pattern recognition, principal component analysis (PCA) was conducted and good separations between all honey samples were obtained. The results of present studies allow the differentiation of honey samples based on the content of sucrose, glucose, and fructose, as well as amino acids such as tyrosine, phenylalanine, proline, and alanine. Our results indicated that the combination of qNMR with chemometric analysis may serve as a supplementary tool in specifying honeys.


Assuntos
Mel , Aminoácidos/análise , Animais , Abelhas , Mel/análise , Espectroscopia de Ressonância Magnética/métodos , Polônia , Análise de Componente Principal
3.
Tumour Biol ; 36(8): 5971-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25740060

RESUMO

The search for novel drug candidates is a priority goal for cancer therapy. Natural products isolated from plants are often used as valuable leads for the synthesis of analogs with simpler structure. Two synthetic α-methylene-δ-lactones with chroman-2-one skeleton, designated DL-3 and DL-5, exhibiting strong cytotoxic activity against several cancer cell lines, have been tested alone and in combination with well-known anticancer drugs, 5-fluorouracil, oxaliplatin, and taxol, in breast cancer MCF-7 cells. Parthenolide, a plant-derived α-methylene-γ-lactone, was used as a positive control. The effects on cell proliferation, DNA damage, and apoptosis induction were evaluated. Neither of the tested compounds significantly enhanced the effects produced by taxol, but a strong synergistic effect was observed with 5-fluorouracil and oxaliplatin. Only small differences between the actions of both α-methylene-δ-lactones were found. The synergistic effects produced by these compounds in MCF-7 cells were stronger as compared with parthenolide. Our findings show that simple and easy-to-obtain synthetic compounds with α-methylene-δ-lactone motif can potentiate the efficiency of anticancer drugs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Lactonas/administração & dosagem , Células MCF-7/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Fluoruracila/administração & dosagem , Humanos , Lactonas/síntese química , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Paclitaxel/administração & dosagem
4.
Bioorg Med Chem ; 22(23): 6545-6551, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25456075

RESUMO

Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of D-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4-aminocyclohexyl-D-alanine (D-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2',6'-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-D-ACAla showed high affinity for both, µ- and δ-opioid receptors (MOR and DOR, respectively) and moderate affinity for the κ-opioid receptor (KOR), while analog with Dmt and cis-D-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity.


Assuntos
Alanina/análogos & derivados , Cicloexanos/química , Peptídeos Opioides/química , Alanina/síntese química , Alanina/química , Ciclização , Cicloexanos/síntese química , Humanos , Peptídeos Opioides/síntese química , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Estereoisomerismo
5.
Bioorg Med Chem ; 22(17): 4803-9, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25047937

RESUMO

In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-ß-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-ß-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-ß-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-ß-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the µ-opioid receptor (MOR) antagonist, ß-funaltrexamine (ß-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail suspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the δ-selective antagonist, naltrindole (NLT) and κ-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the δ- and κ-receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-ß-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies.


Assuntos
Analgésicos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Prolina/química , Analgésicos/síntese química , Analgésicos/química , Animais , Antidepressivos/síntese química , Antidepressivos/química , Relação Dose-Resposta a Droga , Cobaias , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Oligopeptídeos/síntese química , Ratos , Ratos Wistar , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Natação
6.
Food Chem ; 439: 138141, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38061302

RESUMO

Garlic is one of the most popular vegetables worldwide, which contains many bioactive compounds. The chemical composition of garlic varies significantly depending on conditions in the growing locality and other factors. In this paper, the garlic samples were classified based on their geographical origin using principal component analysis (PCA), and significant differences in metabolite composition were found. Quantitative analysis highlighted that Polish garlics have the highest level of sulfur components, similar to Spanish garlic Egyptian garlic exhibited the lowest content of identified metabolites, while Madeira garlic was rich in carbohydrates and amino acids. Chinese garlic had low sugar content but a higher quantity of amino acids and choline. The findings highlight the association between food composition and environmental conditions and can be used to classify garlic based on its origin.


Assuntos
Alho , Alho/química , Antioxidantes/química , Carboidratos , Aminoácidos/análise
7.
ChemMedChem ; 19(7): e202300519, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38126948

RESUMO

Synthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds with anticancer potential. We reasoned that such bifunctional conjugates may have enhanced cytotoxic activity. The title compounds were synthesized in a four step reaction sequence. ß-Ketophosphonate, obtained from methyl N-tosylnicotinate and diethyl methylphosphonate, was reacted with various aldehydes giving 3-diethoxyphosphoryl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones as keto-enol tautomers. Later, these compounds were transformed into 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones applying the Horner-Wadsworth-Emmons methodology. Then, the cytotoxicity of the new compounds was assessed on two cancer cell lines, promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7, and for comparison, on human umbilical vein endothelial cells HUVEC. The most active and selective analog, 2-ethyl-3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one 4 a was chosen for more detailed studies on HL-60 cell line, to determine molecular mechanisms of its anticancer activity. It was shown that 4 a strongly inhibited proliferation and induced apoptosis which could be attributed to its ability to cause DNA damage.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Estrutura Molecular , Relação Estrutura-Atividade , Células Endoteliais , Antineoplásicos/química , Células HL-60 , Proliferação de Células
8.
Bioorg Med Chem ; 20(16): 5017-26, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22789709

RESUMO

A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel-Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC(50) values below 1 µM, mainly against leukemia and MCF-7 cell lines. Investigation of structure-activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cromonas/síntese química , Cromonas/farmacologia , Cumarínicos/química , Antibacterianos/química , Antineoplásicos/química , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 219: 113429, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852973

RESUMO

Herein we report an efficient synthesis of a series of regioisomeric N,O-syn and N,O-anti 3-diethoxyphosphorylfuroquinoline-4,9-diones combining furoquinoline-5,8-dione skeleton, present in several highly cytotoxic compounds, with diethoxyphosphoryl moiety. The cytotoxic activity of the obtained analogs was tested against two human cancer cell lines: promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7 and for comparison on human umbilical vein endothelial cells HUVEC and mammary gland/breast MCF-10 A cells. Several diethoxyphosphorylfuroquinoline-4,9-diones proved to be highly cytotoxic for cancer cells with IC50 values even below 0.1 µM. Interestingly, N,O-syn 3-diethoxyphosphorylfuroquinoline-4,9-diones were 3- to 7-fold more active against HL-60 cells than the respective N,O-anti regioisomers. The most promising analogs 9c and 9i, with the highest cancer/healthy cells cytotoxicity ratio, were further evaluated to establish their mode of action. In HL-60 cells these analogs enhanced intracellular ROS generation and NAD(P)H:quinone oxidoreductase 1 (NQO1) depletion which led to the cell cycle arrest in the S-phase, reduced cell proliferation, DNA damage and apoptosis.


Assuntos
Antineoplásicos/síntese química , Quinolonas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Conformação Molecular , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinolonas/metabolismo , Quinolonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
10.
ChemMedChem ; 14(6): 645-662, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30702807

RESUMO

Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure-activity relationships.


Assuntos
Inibidores Enzimáticos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazinas , Timidilato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Oxazinas/síntese química , Oxazinas/química , Oxazinas/farmacologia , Relação Estrutura-Atividade
11.
Bioorg Med Chem ; 16(9): 4872-82, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18396404

RESUMO

A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6a-g'' and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10a-c and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3a-g. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner-Wadsworth-Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5a-g'' or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9a-c. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC(50) values lower than 6 microM. Structure-activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13a-e, previously obtained in our laboratory, are discussed.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Lactamas/síntese química , Lactamas/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Concentração Inibidora 50 , Lactamas/química , Lactonas/química , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Camundongos , Estrutura Molecular , Padrões de Referência , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Acta Crystallogr C Struct Chem ; 74(Pt 8): 907-916, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30080165

RESUMO

The novel crystal structures of ethyl (S)-P-(4-oxo-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-3-yl)-N-[(R)-1-phenylethyl]phosphonamidate, C20H20N3O3PS, I, and diethyl (4-isopropyl-2-oxo-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidin-3-yl)phosphonate, C18H25N2O4PS, II, were characterized by X-ray diffraction analysis. The crystal packing of I is dominated by two infinite stacks composed of symmetry-independent molecules linked by distinctively different hydrogen-bond systems. The structure of II shows a ladder packing topology similar to those observed in related phosphorylated azaheterocycles. Structural studies are supplemented by calculations on the interactions stabilizing the molecular assemblies using the PIXEL method. Additionally, fingerprint plots derived from the Hirshfeld surfaces were generated for each structure to characterize the crystal packing arrangements in detail. The aromaticities of the heterocyclic moieties have been investigated using HOMA and HOMHED parametrization and compared with structures reported previously.

13.
Acta Biochim Pol ; 64(1): 41-48, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27815964

RESUMO

Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Naftoquinonas/farmacologia , Ácidos Fosforosos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Furanos , Células Hep G2 , Humanos , Indóis , Naftoquinonas/química , Neovascularização Patológica/tratamento farmacológico , Ácidos Fosforosos/química
14.
Eur J Med Chem ; 120: 51-63, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27187858

RESUMO

In this paper we report an efficient and general synthesis of substituted 3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo [f]indole-4,9-diones which integrate the natural 1,4-naphtalenedione scaffold, present in several anticancer agents with the phosphonate moiety. The cytotoxicity of such hybrid molecules was tested against two leukemia cell lines, HL-60 and NALM-6 and against a breast adenocarcinoma MCF-7 cell line. Selected compounds were also tested on normal human cells: HUVEC and MCF-10A. In general, naphthofuran-4,9-diones showed much higher cytotoxic activity (IC50 values below 10 µM) than benzoindole-4,9-diones. The most promising 2-(2-chlorophenyl)-3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-dione, with the highest cytotoxic activity in the MTT test, was chosen for further evaluation of its anticancer potential. This compound, tested on HL-60 and MCF-7 cells inhibited cell proliferation, generated DNA damage and induced apoptosis. The suggested mechanism of its cytotoxic activity was the generation of intracellular reactive oxygen species and the induction of mitochondrial membrane potential dissipation.


Assuntos
Antineoplásicos/química , Indóis/farmacologia , Organofosfonatos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Indóis/química , Organofosfonatos/química , Relação Estrutura-Atividade
15.
Chem Biol Drug Des ; 86(5): 961-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25832885

RESUMO

The limited success of the currently used antitumor therapies is the driving force for organic chemists to seek new lead structures with anticancer potential. Two α-methylene-γ-lactams with an additional nitrogen atom in the lactam ring, 5-vinyl-1,2-diphenyl-4-methylenepyrazolidin-3-one (2a) and 5-phenyl-1,2-diphenyl-4-methylenepyrazolidin-3-one (2b) have been synthesized. Their anticancer activity was assessed in MCF-7 cells. Both compounds inhibited cell proliferation and induced DNA damage and apoptosis, with 2a being the more potent analog. Synergistic effects of 2a used in combination with known anticancer drugs, 5-fluorouracil, taxol, and oxaliplatin were evaluated. Compound 2a significantly enhanced the antitumor action of oxaliplatin and 5-fluorouracil, but not taxol.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Pirazolonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Pirazolonas/química
16.
Eur J Med Chem ; 92: 565-74, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25602933

RESUMO

Three series of new 4-methylidenepyrazolidin-3-ones with various substitution patterns were synthesized and tested for the cytotoxic activity against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer cell line. Several obtained methylidenepyrazolidinones exhibited high cytotoxic activity with IC50 values below 10 µM, mainly against HL-60 leukemia cell line and two of them, 18d,e, displayed IC50 ≤ 5 µM, against all tested cell lines. Structure-activity relationship studies revealed that the presence of phenyl substituents on both ring nitrogen atoms and vinyl or phenyl substituents in position 5 are crucial for high activity. Selected methylidenepyrazolidinones were also tested on normal human umbilical vein endothelial cells (HUVEC) and pyrazolidinone 18a was found to be 5-fold more toxic against HL-60 than normal cells.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
17.
Basic Clin Pharmacol Toxicol ; 113(6): 391-400, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24034139

RESUMO

Natural products are important leads in drug discovery. The search for effective plant-derived anticancer agents or their synthetic analogues has continued to be of interest to biologists and chemists for a long time. In this report, cytotoxicity and anticancer activity of new synthetic α-methylene-δ-lactones was tested against two breast cancer cell lines, invasive, hormone-independent MDA-MB-231 and hormone-dependent MCF-7. Cytotoxicity was examined using MTT assay. The ability to induce apoptosis and changes in mitochondrial membrane potential was studied by flow cytometry. The expression levels of pro- and anti-apoptotic genes were determined by quantitative real-time PCR. Cancer cell migration and invasion were assessed by wound healing and Matrigel assays. Additionally, secretion of proteins associated with invasiveness, metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) was investigated using commercial ELISA kits and MMP-9 activity by gelatin zymography. A natural sesquiterpene lactone, parthenolide, was used as a positive control. Screening results showed all four analogues to be highly cytotoxic. The most potent compound of the series, 1-isopropyl-2-methylene-1,2-dihydrobenzochromen-3-one, designated DL-3, which reduced the number of viable MDA-MB-231 and MCF-7 cells with the IC50 values of 5.3 µM and 3.54 µM, respectively, was selected for further research. DL-3 activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. DL-3 also inhibited the movement of both types of breast cancer cells. Suppression of cell migration and invasion was the result of the decreased secretion of enzymes responsible for the degradation of the extracellular matrix, MMP-9 and uPA. These findings show that the synthetic α-methylene-δ-lactone, DL-3, displays potential to be further explored in the development of new anticancer agents.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/uso terapêutico , Células MCF-7/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Feminino , Humanos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
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