RESUMO
In this work, a preparative supercritical fluid chromatography (SFC) method was first developed to separate a series of chiral compounds evaluated as lactam-based P2RX7 antagonists. Subsequently, high-performance liquid chromatography, SFC, and capillary electrophoresis (CE) were comparatively investigated as QC tools to determine the enantiomeric purity of the separated isomers, including analytical performance and greenness. The screening of the best conditions was carried out in liquid and SFC on the nine derivatives and the amylose tris(3,5-dimethylphenylcarbamate)-based chiral stationary phase was found to be highly efficient. The same screening was carried out in CE and very different conditions, either in acidic or basic background electrolyte and different cyclodextrins used as chiral selectors, allowed the separation of six of the nine derivatives. 1-((3,4-Dichlorophenyl)carbamoyl)-5-oxopyrrolidine-2-carboxylic acid (compound 1) was chosen as a probe, and its semi-preparative separation by SFC and enantiomeric verification using the three techniques are presented. Its limit of detection and limit of quantification are calculated for each method. Finally, the greenness of each quality control method was evaluated.
Assuntos
Amilose , Cromatografia com Fluido Supercrítico , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia com Fluido Supercrítico/métodos , Estereoisomerismo , Eletroforese CapilarRESUMO
RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age-related diseases. For the development of small-molecule RAGE antagonists, we employed protein-templated dynamic combinatorial chemistry (ptDCC) using RAGE's VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde-modified AGE)-sRAGE (solubleRAGE) (AGE2-BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small-molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years.
Assuntos
Transdução de Sinais , Receptor para Produtos Finais de Glicação Avançada/química , Receptor para Produtos Finais de Glicação Avançada/metabolismoRESUMO
As new environmentally friendly and effective antifungal agents are deeply needed, efficient ecofriendly strategies were designed to access two series of compounds inspired from natural γ-lactams. Designed compounds were fully characterized and evaluated as antifungal candidates against Zymoseptoria tritici, the main pathogen on wheat crops. The targeted derivatives were prepared from natural resources using green solvents, simple procedures, and limited purification steps. These bio-inspired compounds revealed as good candidates for further development of efficient crop protection products. Indeed, the HIT compounds exhibited IC50 around 1⠵g/mL and were more active than the references tebuconazole and bixafen towards some multidrug-resistant strains. Two dozen of derivatives have been obtained for each series and allowed to establish early structure-activity relationships useful for the development of next generation of γ-lactam derivatives with improved efficacy.
Assuntos
Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Lactamas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Lactamas/síntese química , Lactamas/química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Plant resistance inducers are among the most promising alternatives to develop sustainable crop protection. Here, we examined the ability of saccharin, a metabolite derived from probenazole, to protect wheat against Zymoseptoria tritici, the most frequently occurring and damaging foliar pathogen on this crop. The experiments were performed in the greenhouse by treating seedlings of the wheat cultivar 'Alixan' with 15 mM of saccharin 2 days before challenge inoculation with the Z. tritici pathogenic strain T02596. Foliar application of saccharin resulted in 77% lower disease severity than in nontreated control plants. In vitro and in planta assays showed that saccharin did not exhibit any direct antifungal effect on spore germination or hyphal growth. Molecular investigations from 2 to 7 days posttreatment (dpt) revealed that saccharin treatment upregulates the expression of genes encoding for lipoxygenase (LOX) at all sampled time points and pathogenesis-related protein 1 (PR1) at 7 dpt, in both noninfectious and infectious contexts, as well as peroxidase (POX2) in noninfectious conditions. However, saccharin did not induce significant change in the expression of PAL gene encoding for phenylalanine ammonia-lyase. Our findings report for the first time the potential of saccharin to confer protection in wheat against Z. tritici through an elicitation and priming of LOX and PR gene-related defense pathways. Additional investigations would provide a better deciphering of defense mechanisms activated by this molecule in wheat against Z. tritici.
Assuntos
Sacarina , Triticum , Ascomicetos , Mecanismos de Defesa , Doenças das PlantasRESUMO
The treatment of benzylidenemalononitriles with phenylhydrazines in refluxing ethanol did not provide pyrazole derivatives, but instead furnished hydrazones. The structure of hydrazones was secured by X-ray analysis. The chemical proof was also obtained by direct reaction of 3,4,5-trimethoxybenzaldehyde with 2,4-dichlorophenylhydrazine. Newly synthesized hydrazones were tested against eight Candida spp. strains in a dose response assay to determine the minimum inhibitory concentration (MIC99). Five compounds were identified as promising antifungal agents against Candida spp. (C. albicans SC5314, C. glabrata, C. tropicalis, C. parapsilosis and C. glabrata (R azoles)), with MIC99 values ranging from 16 to 32 µg/mL and selective antifungal activity over cytotoxicity.
Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Farmacorresistência Fúngica , Hidrazonas/farmacologia , Pirazóis/química , Antifúngicos/química , Candida/crescimento & desenvolvimento , Hidrazonas/química , Testes de Sensibilidade MicrobianaRESUMO
A broad range of chalcones and derivatives were easily and rapidly synthesized, following Claisen-Schmidt condensation of (hetero)aryl ketones and (hetero)aryl aldehydes using a ultrasound probe. A comparison was made with classical magnetic stirring experiments, and an optimization study was realized, showing lithium hydroxide to be the best basic catalyst of the studied condensations. By-products of the reactions (ß-hydroxy-ketone, diketones, and cyclohexanols) were also isolated. All compounds were evaluated in vitro for their ability to inhibit human farnesyltransferase, a protein implicated in cancer and rare diseases and on the NCI-60 cancer cell lines panel. Molecules showed inhibitory activity on the target protein and cytostatic effect on different cell lines with particular activity against MCF7, breast cancer cells.
Assuntos
Antineoplásicos/síntese química , Chalconas/química , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/metabolismo , Chalconas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/metabolismo , Humanos , Simulação de Acoplamento Molecular , Sonicação , Relação Estrutura-AtividadeRESUMO
Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent - hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the -NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate "fungicide-like" properties and were devoted of cytotoxicity.
Assuntos
Antifúngicos/farmacologia , Hidrazonas/farmacologia , Pirrolidinonas/farmacologia , Antifúngicos/síntese química , Desenho de Fármacos , Fungos/efeitos dos fármacos , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirrolidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones. Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested. Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range. The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules. Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Moduladores de Tubulina/farmacologia , Acetatos/química , Antineoplásicos/química , Benzofenonas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/química , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/químicaRESUMO
In the incessant search for innovative cancer control strategies, this study was devoted to the design, synthesis and pharmacological evaluation of dual inhibitors of farnesyltransferase and tubulin polymerization (FTI/MTIs). A series of indolizine-phenothiazine hybrids 16 (amides) and 17 (ketones) has been obtained in a 4-step procedure. The combination of the two heterocycles provided potent tubulin polymerization inhibitors with similar efficiency as the reference phenstatin and (-)-desoxypodophyllotoxin. Ketones 17 were also able to inhibit human farnesyltransferase (FTase) in vitro. Interestingly, three molecules 17c, 17d and 17f were very effective against both considered biological targets. Next, nine indolizine-phenothiazine hybrids 16c, 16f, 17a-f and 22b were evaluated for their cell growth inhibition potential on the NCI-60 cancer cell lines panel. Ketones 17a-f were the most active and displayed promising cellular activities. Not only they arrested the cell growth of almost all tested cancer cells, but they displayed cytotoxicity potential with GI50 values in the low nanomolar range. The most sensitive cell lines upon treatment with indolizine-phenothiazine hybrids were NCI-H522 (lung cancer), COLO-205 and HT29 (colon cancer), SF-539 (human glioblastoma), OVCAR-3 (ovarian cancer), A498 (renal cancer) and especially MDA-MB-435 (melanoma). Demonstrating the preclinical effectiveness of these dual inhibitors can be crucial. A single dual molecule could induce a synergy of antitumor activity, while increasing the effectiveness and reducing the toxicity of the classical combo treatments currently used in chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Indolizinas/farmacologia , Fenotiazinas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Farnesiltranstransferase/química , Farnesiltranstransferase/metabolismo , Humanos , Indolizinas/síntese química , Indolizinas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismoRESUMO
CD-CZE methods were developed for complete stereoisomeric separations of a series of six γ-lactam analogues, of which some were neutral, or cationic depending on the background electrolyte nature. The tested cyclodextrin was the versatile sulfobutylether- ß-CD, used either in a phosphate buffer using capillaries dynamically coated with polyethylene oxide or in a borate buffer using uncoated capillaries. Long-end and short-end modes and concentration variations of chiral selectors allowed finding conditions of complete separation of four out of the six derivatives (i.e., 1, 2, 3, and 4) in short run times, confirming their broad range of applications. To separate the two last compounds, the highly sulfated- γ-CD was examined as chiral selector in acidic phosphate conditions. The enantiomers of the γ-lactam analogues 5 and 6 were baseline resolved with 5.5 and 4%, respectively as concentration in the buffer.
Assuntos
Antifúngicos/isolamento & purificação , Eletroforese Capilar/métodos , beta-Ciclodextrinas/química , Ânions/química , Antifúngicos/análise , Antifúngicos/química , Ácido Pirrolidonocarboxílico/análise , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/isolamento & purificação , EstereoisomerismoRESUMO
An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.
RESUMO
Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected by two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration were at first selected as the key steps for these strategies. Ultimately the intramolecular α-amidoalkylation reaction was achieved through the arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brønsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6-membered aza-heterocycles, to the formation of scarce spiro-5-membered analogues which show promising inhibitory activities on human farnesyltransferase in the nanomolar range demonstrating improved IC50 values of up to 1.5 nM.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Isoindóis/química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Modelos Moleculares , Conformação MolecularRESUMO
Unprecedented triazinyl-isoxazoles were afforded via an effective cycloaddition reaction between nitrile oxides and the scarcely described 2-ethynyl-4,6-dimethoxy-1,3,5-triazine as dipolarophile. The biological evaluation of the newly synthesized compounds showed that the inhibition of human farnesyltransferase by zinc complexation could be improved with triazine-isoxazole moieties. The replacement of the isoxazole unit by a pyrrolidin-2-one was detrimental to the inhibitory activity while the pyrrolidin-2-thione derivatives conserved the biological potential. The potential of selected compounds to disrupt protein farnesylation in Chinese hamster ovary (CHO) cells transfected with pEGFP-CAAX was also evaluated.
Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Isoxazóis/farmacologia , Pirrolidinonas/farmacologia , Triazinas/farmacologia , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Farnesiltranstransferase/metabolismo , Humanos , Isoxazóis/química , Estrutura Molecular , Pirrolidinonas/química , Relação Estrutura-Atividade , Triazinas/químicaRESUMO
Resistance of the opportunistic pathogen Candida albicans to antifungal drugs has increased significantly in recent years. After screening 55 potential antifungal compounds from a chemical library, 2,3-dihydroxy-4-methoxybenzaldehyde (DHMB) was identified as having potential antifungal activity. The properties of DHMB were then assessed in vitro and in vivo against C. albicans overgrowth and intestinal inflammation. Substitution on the aromatic ring of DHMB led to a strong decrease in its biological activity against C. albicans. The MIC of DHMB was highly effective at eliminating C. albicans when compared to that of caspofungin or fluconazole. Additionally, DHMB was also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. DHMB was administered to animals at high doses. This compound was not cytotoxic and was well-tolerated. In experimental dextran sodium sulphate (DSS)-induced colitis in mice, DHMB reduced the clinical and histological score of inflammation and promoted the elimination of C. albicans from the gut. This finding was supported by a decrease in aerobic bacteria while anaerobic bacteria populations were re-established in mice treated with DHMB. DHMB is a small organic molecule with antifungal properties and anti-inflammatory activity by exerting protective effects on intestinal epithelial cells.
Assuntos
Benzaldeídos/administração & dosagem , Candidíase/tratamento farmacológico , Inflamação/tratamento farmacológico , Intestinos/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Antifúngicos/administração & dosagem , Antifúngicos/química , Benzaldeídos/química , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Candidíase/microbiologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Inflamação/microbiologia , Inflamação/patologia , Intestinos/microbiologia , Intestinos/patologia , CamundongosRESUMO
BACKGROUND: To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of γ-aminobutyric acid, has never been studied in the context of plant protection. RESULTS: The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance. CONCLUSION: Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture. © 2018 Society of Chemical Industry.
Assuntos
Ascomicetos/fisiologia , Doenças das Plantas/imunologia , Ácido Pirrolidonocarboxílico/imunologia , Ácido Salicílico/imunologia , Triticum/imunologia , Resistência à Doença , Doenças das Plantas/microbiologia , Ácido Pirrolidonocarboxílico/química , Ácido Salicílico/química , Triticum/microbiologiaRESUMO
Two kitchen garden soils (A and B) sampled in contaminated areas were amended using phosphates in sustainable quantities in order to reduce the environmental availability of potentially toxic inorganic elements (PTEs) and to favour the availability of alkali, alkali earth and micronutrients. The environmental availability of PTEs was evaluated using a potential plant for revegetation of contaminated soils (ryegrass) and a mixture of low molecular weight organic acids. Despite the highest contamination level of B, the concentration of metals was highest in the ryegrass shoots grown on A for the two harvests. These results correlated well with those obtained using low molecular weight organic acids for Cd, Zn and Cu, whereas this mixture failed to represent the transfer of nutrients due to the presence of biological and physiological mechanisms. The statistical differences between the biomass of ryegrass obtained at the first and the second harvests were attributed to the decrease of available potassium, implicated in the growth and development of plants. Phosphates increased the ratios Zn/Cd, Zn/Pb and Zn/Cu up to 176 ± 48, 38 ± 6 and 80 ± 12, respectively, and made possible the reduction of the concentration of Cd and Pb in the shoots of ryegrass by 22% and 25%, respectively. The concentration of Zn in the shoots of ryegrass from the first and the second harvests grown on soil A were in the range 1050-2000 mg kg-1, making this plant a potential biomass to (i) produce biosourced catalysts for organic chemistry applications in a circular economy concept and (ii) limit human exposure to commercial Lewis acids. A preliminary application was identified.
Assuntos
Lolium/crescimento & desenvolvimento , Metais Pesados/metabolismo , Fosfatos/administração & dosagem , Poluentes do Solo/química , Solo/química , Biodegradação Ambiental , Biomassa , Cádmio/metabolismo , Fenômenos Químicos , Cobre/metabolismo , Poluição Ambiental , Humanos , Chumbo/metabolismo , Lolium/metabolismo , Desenvolvimento Sustentável , Zinco/metabolismoRESUMO
In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.
Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Ácido Pirrolidonocarboxílico/análogos & derivados , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/química , Humanos , Modelos Biológicos , Estrutura Molecular , Conformação Proteica , Ácido Pirrolidonocarboxílico/metabolismoRESUMO
A new family of indolizine-chalcones was designed, synthesized and screened for the inhibitory potential on human farnesyltransferase in vitro to identify potent antitumor agents. The most active compound was phenothiazine 2a, exhibiting an IC50 value in the low nanomolar range, similar to that of known FTI-276, highly potent farnesyltransferase inhibitor. The newly synthesized indolizine-chalcones 2a-d constitute the most efficient inhibitors of farnesyltransferase bearing a phenothiazine unit known to date.
Assuntos
Chalconas/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Indolizinas/farmacologia , Chalconas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Farnesiltranstransferase/metabolismo , Humanos , Indolizinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the "CH2" bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25nM against the melanoma MDA-MB-435 cell line.
Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Tubulina (Proteína)/metabolismo , 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 , Humanos , Modelos Moleculares , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Polimerização/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
New phenothiazine derivatives 6-20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2'-fluoro-4'-methoxy substitution in compound 6 and the 2'-trifluoromethyl-4'-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6-8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke's type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.