RESUMO
High extracellular concentrations of adenosine triphosphate (ATP) in the tumor microenvironment generate adenosine by sequential dephosphorylation of CD39 and CD73, resulting in potent immunosuppression to inhibit T cell and natural killer (NK) cell function. CD73, as the determining enzyme for adenosine production, has been shown to correlate with poor clinical tumor prognosis. Conventional inhibitors as analogues of adenosine 5'-monophosphate (AMP) may have a risk of further metabolism to adenosine analogues. Here, we report a new series of malonic acid non-nucleoside inhibitors coordinating with zinc ions of CD73. Compound 12f was found to be a superior CD73 inhibitor (IC50 = 60 nM) by structural optimization, and its pharmacokinetic properties were investigated. In mouse tumor models, compound 12f showed excellent efficacy and reversal of immunosuppression in combination with chemotherapeutic agents or checkpoint inhibitors, suggesting that it deserves further development as a novel CD73 inhibitor.
Assuntos
5'-Nucleotidase , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Animais , Humanos , Camundongos , Malonatos/farmacologia , Malonatos/química , Malonatos/síntese química , Zinco/química , Zinco/metabolismo , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Descoberta de Drogas , Linhagem Celular TumoralRESUMO
The new steroidal pyrimidine derivatives (4-6) were synthesized by the reaction of steroidal thiosemicarbazones with (2-methyl) diethyl malonate in absolute ethanol. After characterization by spectral and analytical data, the DNA interaction studies of compounds (4-6) were carried out by UV-vis, fluorescence spectroscopy, hydrodynamic measurements, molecular docking and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.31×103M-1, 1.93×103M-1 and 2.05×103M-1, respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis demonstrated that compound 4 showed a strong interaction during the concentration dependent cleavage activity with pBR322 DNA. The molecular docking study suggested the intercalation of steroidal pyrimidine moiety in the minor groove of DNA. During in vitro cytotoxicity, compounds (4-6) revealed potential toxicity against the different human cancer cells (MTT assay). During DAPI staining, the nuclear fragmentations on cells occurred after treatment with compounds 4 and 5. Western blotting analysis clearly indicates that compound 4 causes apoptosis in MCF-7 cancer cells. The results revealed that compound 4 has better prospectus to act as a cancer chemotherapeutic candidate, which warrants further in vivo anticancer investigations.
Assuntos
Antineoplásicos/química , DNA/efeitos dos fármacos , Pirimidinas/química , Tiossemicarbazonas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Malonatos/síntese química , Malonatos/química , Malonatos/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Esteroides/síntese química , Esteroides/química , Esteroides/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologiaRESUMO
A series of new malonamide derivatives were synthesized by Michael addition reaction of N(1),N(3)-di(pyridin-2-yl)malonamide into α,ß-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against α-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of α-glucosidase enzyme. Among all the compounds, 4K (IC50=11.7 ± 0.5 µM) was found out as the most active one compared to standard drug acarbose (IC50=840 ± 1.73 µM). Further cytotoxicity of 4a-4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained.
Assuntos
Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Malonatos/síntese química , Malonatos/farmacologia , alfa-Glucosidases/metabolismo , Células 3T3 , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/química , Humanos , Malonatos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Three platinum(II) complexes of (1R,2R)-N(1)-cyclopentyl-1,2-cyclohexanediamine with malonate derivatives were designed, synthesized and spectrally characterized. MTT assay showed that the complexes possessed positive cytotoxic effect on the four human solid tumor cell lines. Among the complexes, complex 2 demonstrated the strongest cytotoxic activity compared to cisplatin and oxaliplatin against HepG2 cell line (IC50=3.04µM). Furthermore, the results of gel electrophoresis revealed that complex 2 interacted with DNA in a different mode from that of cisplatin. Mechanism studies of cell proliferation inhibition and cellular uptake indicated that complex 2 entered HepG2 cell more efficiently than cisplatin, exhibited massive G2 accumulation and then induced apoptosis.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cicloexilaminas/farmacologia , Malonatos/farmacologia , Compostos Organoplatínicos/farmacologia , Platina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cicloexilaminas/síntese química , Cicloexilaminas/química , Clivagem do DNA/efeitos dos fármacos , DNA Super-Helicoidal/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Malonatos/síntese química , Malonatos/química , Compostos Organoplatínicos/síntese química , Relação Estrutura-AtividadeRESUMO
A water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)} was synthesized. The anticancer activity and toxicity were evaluated by comparing its interaction with DNA, cytotoxicity against four human cancer cell lines, antitumor efficiency in human gastric carcinoma NCI-N87 xenografts in nude mice, and preliminary side-effects in rats to those of its 4R,5R-optical isomer which is under preclinical development. Both isomers induce condensation of DNA to the same extent and have similar cytotoxicity, but show different antitumor activity and toxicity, probably owing to the difference in respective pharmacokinetic profiles. 4S,5S-Isomer seems to exhibit superior antitumor activity and less toxicity than 4R,5R-optical isomer as well as the parent heptaplatin. These results imply that 4S,5S-configuration as a new drug candidate may be better than 4R,5R-counterpart.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Malonatos/síntese química , Malonatos/farmacologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Dicroísmo Circular , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Malonatos/química , Compostos Organoplatínicos/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierAssuntos
Aminoquinolinas/química , Corantes Fluorescentes/química , Malonatos/química , Microscopia Confocal , Compostos de Sulfidrila/análise , Aminoquinolinas/síntese química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Humanos , Malonatos/síntese química , Fótons , Teoria Quântica , Soluções/químicaRESUMO
A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing the enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Malonatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Indóis/síntese química , Indóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , L-Lactato Desidrogenase/metabolismo , Lactato Desidrogenase 5 , Ácido Láctico/antagonistas & inibidores , Ácido Láctico/biossíntese , Malonatos/síntese química , Malonatos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
Assuntos
Anti-Inflamatórios/síntese química , Compostos de Benzilideno/síntese química , Malonatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Sítios de Ligação , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Malonatos/síntese química , Malonatos/química , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.
Assuntos
L-Lactato Desidrogenase/antagonistas & inibidores , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Isoenzimas/antagonistas & inibidores , Lactato Desidrogenase 5 , Espectroscopia de Ressonância Magnética , Malonatos/síntese química , Malonatos/química , Malonatos/farmacologia , Modelos Moleculares , Estrutura Molecular , Niacinamida/química , Ácido Oxâmico/análogos & derivados , Ácido Oxâmico/síntese química , Ácido Oxâmico/química , Ácido Oxâmico/farmacologia , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Ressonância de Plasmônio de SuperfícieRESUMO
Six diam(m)ineplatinum(II) complexes with 2,2-bis(hydroxymethyl)malonate as the leaving group were synthesized and characterized by elemental analysis, FAB-MS, FT-IR, (1)H and (13)C NMR along with a single crystal X-ray diffraction for a representative compound. All the complexes were evaluated for the cytotoxicity against human cancer cell lines A549/ATCC, HT-29, SGC-7901. The activity is related to the nature of the am(m)ine ligand. cis-[Pt(II)(1R,2R-Diaminocyclohexane)·2,2-bis(hydroxymethyl)malonate] (complex 5) exhibits the greatest activity among those six complexes, and is even more active than its parent compound oxaliplatin. LD(50) was found to be 115 mg/kg by iv administration to ICR mice, much larger than that of oxaliplatin (LD(50)=19 mg/kg).
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Malonatos/síntese química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Malonatos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Relação Estrutura-AtividadeRESUMO
In the design of inhibitors of phosphosugar metabolizing enzymes and receptors with therapeutic interest, malonate has been reported in a number of cases as a good and hydrolytically-stable surrogate of the phosphate group, since both functions are dianionic at physiological pH and of comparable size. We have investigated a series of malonate-based mimics of the best known phosphate inhibitors of class II (zinc) fructose-1,6-bis-phosphate aldolases (FBAs) (e.g., from Mycobacterium tuberculosis), type I (zinc) phosphomannose isomerase (PMI) from Escherichia coli, and phosphoglucose isomerase (PGI) from yeast. In the case of FBAs, replacement of one phosphate by one malonate on a bis-phosphorylated inhibitor (1) led to a new compound (4) still showing a strong inhibition (K(i) in the nM range) and class II versus class I selectivity (up to 8×10(4)). Replacement of the other phosphate however strongly affected binding efficiency and selectivity. In the case of PGI and PMI, 5-deoxy-5-malonate-D-arabinonohydroxamic acid (8) yielded a strong decrease in binding affinities when compared to its phosphorylated parent compound 5-phospho-D-arabinonohydroxamic acid (2). Analysis of the deposited 3D structures of the kinetically evaluated enzymes complexed to the phosphate-based inhibitors indicate that malonate could be a good phosphate surrogate only if phosphate is not tightly bound at the enzyme active site, such as in position 7 of compound 1 for FBAs. These observations are of importance for further design of inhibitors of phosphorylated-compounds metabolizing enzymes with therapeutic interest.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfato Aldolase/antagonistas & inibidores , Glucose-6-Fosfato Isomerase/antagonistas & inibidores , Malonatos/síntese química , Manose-6-Fosfato Isomerase/antagonistas & inibidores , Animais , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Escherichia/enzimologia , Humanos , Concentração Inibidora 50 , Malonatos/química , Malonatos/farmacologia , Modelos Biológicos , Estrutura Molecular , Leveduras/enzimologiaRESUMO
A novel water-soluble heptaplatin analogue, cis-[(4R,5R)-4,5-bis-(aminomethyl)-2-isopropyl-1,3-dioxolane](3-hydroxy-1,1-cyclobutanedicarboxylato)platinum(II), has been synthesized and biologically evaluated. The complex shows more activity and less toxicity than its parent drug heptaplatin, exhibiting the great potential for further development.
Assuntos
Antineoplásicos/farmacologia , Malonatos/farmacologia , Compostos Organoplatínicos/farmacologia , Água/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Malonatos/síntese química , Malonatos/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Taxa de SobrevidaRESUMO
Multifunctional and water-soluble superparamagnetic iron oxide (SPIO) nanocarriers were developed for targeted drug delivery and positron emission tomography/magnetic resonance imaging (PET/MRI) dual-modality imaging of tumors with integrin α(v)ß3 expression. An anticancer drug was conjugated onto the PEGylated SPIO nanocarriers via pH-sensitive bonds. Tumor-targeting ligands, cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) peptides, and PET 64Cu chelators, macrocyclic 1,4,7-triazacyclononane-N, N', Nâ³-triacetic acid (NOTA), were conjugated onto the distal ends of the PEG arms. The effectiveness of the SPIO nanocarriers as an MRI contrast agent was evaluated via an in vitro r2 MRI relaxivity measurement. cRGD-conjugated SPIO nanocarriers exhibited a higher level of cellular uptake than cRGD-free ones in vitro. Moreover, cRGD-conjugated SPIO nanocarriers showed a much higher level of tumor accumulation than cRGD-free ones according to non-invasive and quantitative PET imaging, and ex vivo biodistribution studies. Thus, these SPIO nanocarriers demonstrated promising properties for combined targeted anticancer drug delivery and PET/MRI dual-modality imaging of tumors.
Assuntos
Dextranos/síntese química , Diagnóstico por Imagem/métodos , Doxorrubicina/farmacocinética , Portadores de Fármacos/síntese química , Animais , Meios de Contraste/química , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Integrina alfaVbeta3/metabolismo , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita , Malonatos/síntese química , Camundongos , Camundongos Nus , Modelos Animais , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Peptídeos Cíclicos/química , Tomografia por Emissão de Pósitrons , Distribuição TecidualRESUMO
Malonic acid diamides with two long hydrophobic alkyl chains and a basic polar head group as a new class of non-viral gene transferring compounds have shown high transfection efficiency and moderate toxicity. Based on the results obtained with saturated and unsaturated alkyl residues new derivatives with a more complex head group structure have been synthesized. For this purpose, cationic respectively basic groups were introduced by one or two lysine residues bound via tris(aminoethyl)amine spacer to the malonic acid diamide backbone. By studying in vitro gene delivery an increase of transfection efficacy was observed when using lipids with at least one unsaturated alkyl chain. This leads to cationic lipids exhibiting comparable or even higher transfection efficacies compared to the commercially available transfection agents LipofectAmine™ and SuperFect™. Phase transitions and phase structures of selected compounds have been analyzed and discussed in terms of transfection abilities. Particle size and zeta potential of liposomes and lipoplexes were also determined.
Assuntos
Amidas/farmacologia , Vetores Genéticos/química , Malonatos/farmacologia , Transfecção/métodos , Amidas/síntese química , Amidas/química , Animais , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Vetores Genéticos/síntese química , Humanos , Células LLC-PK1 , Lipossomos , Malonatos/síntese química , Malonatos/química , Tamanho da Partícula , Transição de Fase , SuínosRESUMO
A novel class of KAT modulators (long chain alkylidenemalonates, LoCAMs) has been identified. Variations of the alkyl chain length can change the activity profile from inhibition of both KAT3A/KAT2B (as derivative 2a) to the peculiar profile of pentadecylidenemalonate 1b, the first activator/inhibitor of histone acetyltransferases. Together with the powerful apoptotic effect (particularly notable if considering that anacardic acid and other KAT inhibitors are not cell permeable) appoint them as valuable biological tools to understand the mechanisms of lysine acetyltransferases.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Malonatos/química , Malonatos/farmacologia , Alquilação/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Humanos , Malonatos/síntese química , Células U937RESUMO
Forty-one derivatives of papyriferic acid were prepared based on our previous finding that methyl papyriferate (3) showed potent reversing effect on cytotoxicity of colchicine against multidrug resistance (MDR) human cancer cells (KB-C2), and evaluated for their cytotoxicity and effect on reversing P-gp-mediated MDR against KB-C2 cells. 3-O-(Morpholino-beta-oxopropanoyl)-12beta-acetoxy-3alpha,25-dihydroxy-(20S,24R)-epoxydammarane (37) significantly increased the sensitivity of colchicine against KB-C2 cells by 185-fold at 5microg/mL (7.4microM), and the cytotoxicity of colchicine was recovered to nearly that of sensitive (KB) cells. The other several new amide derivatives also exhibited potent reversal activity comparable to or more potent than methyl papyriferate and verapamil.
Assuntos
Antineoplásicos/química , Malonatos/química , Morfolinas/química , Triterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Malonatos/síntese química , Malonatos/toxicidade , Morfolinas/síntese química , Morfolinas/farmacologia , Triterpenos/síntese química , Triterpenos/farmacologia , Triterpenos/toxicidadeRESUMO
A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.
Assuntos
Antineoplásicos/química , Malonatos/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Malonatos/síntese química , Malonatos/farmacocinética , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinéticaRESUMO
Diethyl alpha-alkynyl-alpha-methoxymalonates (2a--e) were smoothly hydrolyzed and then decarboxylated under alkaline conditions employing 1 N KOH in EtOH to give conjugated allenyl esters (6a--e) in high yields, and similar alkaline treatment of diethyl alpha-alkynyl-alpha-acetylaminomalonates (5a, b, d, e) furnished unexpectedly the oxazoles (7a, b, d, e) having three substituent groups in excellent yields.
Assuntos
Alcinos/síntese química , Ésteres/síntese química , Malonatos/síntese química , Oxazóis/síntese química , Álcalis , Biomimética , Inibidores de Cisteína Proteinase/farmacologia , Hidrólise , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
A new phosphotyrosyl mimetic 4-(alpha-hydroxymalonyl)phenylalanine and its incorporation into a Grb2 SH2 domain-binding tripeptide are presented. In whole-cell studies using malonyl ethyl ester prodrug derivatives, it was observed that the 4-(alpha-hydroxymalonyl)phenylalanyl-containing peptide exhibited greater efficacy than the nonhydroxylated 4-(malonyl)phenylalanyl-containing congener in blocking the association of Grb2 with activated erbB-2 tyrosine kinase. These results are consistent with de-esterification and at least partial intracellular decarboxylation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Malonatos/síntese química , Oligopeptídeos/síntese química , Fenilalanina/análogos & derivados , Fosfotirosina/química , Domínios de Homologia de src , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Linhagem Celular Tumoral , Desenho de Fármacos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Proteína Adaptadora GRB2 , Humanos , Malonatos/química , Malonatos/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Ressonância de Plasmônio de SuperfícieRESUMO
A poly(ethylene oxide)-block-poly(methylidene malonate 2.1.2) block copolymer (PEO-b-PMM 2.1.2) bearing a mannose moiety at the poly(ethylene oxide) chain end was synthesized by sequential anionic polymerization of ethylene oxide (EO) and methylidene malonate 2.1.2 (MM 2.1.2), followed by a coupling reaction between its poly(ethylene oxide) amino- or aldehyde-end group and a sugar derivative. Different coupling procedures, either in organic media or in aqueous micellar solutions, were examined in order to optimize the poly(ethylene oxide) end-glycosylation yield. The micellar size of the functionalized block copolymers was determined by dynamic light scattering.