RESUMEN
N-ribosylation and N-mannosylation compounds have a great role in compounds activity as anticancer. The reaction of 2-thioxo-4-thiazolidinone (rhodanine) derivatives, as aglycon part, was done with ribofuranose and mannopyranose sugars (glycone part) followed by deacetylation without cleavage of the rhodanine under acidic medium. Conformational analysis has been studied using NMR methods (2D, DQF-COSY, HMQC and HMBC). All final the new deprotected nucleosides were screened against leukemia 1210, and were found to be considerably less potent (Ic50% 1.4-10.6 µM) than doxorubicin (Ic50% 0.02 µM). Compounds 10d and 10e which contain ribose moiety have better activity than those with mannose sugar. DFT calculations with B3LYP/6-31 + G (d) level were used to analyze the electronic and geometric characteristics deduced from the stable structure of the compounds. The principal quantum chemical descriptors showed a good correlation with the experimental observations. Rapid Overlay Comparison Similarity (ROCS) study was operated to explain the compounds similarity and to figure out the most important pharmacophoric features.
Asunto(s)
Antineoplásicos/farmacología , Teoría Funcional de la Densidad , Diseño de Fármacos , Manósidos/farmacología , Rodanina/farmacología , Ribonucleósidos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Manósidos/química , Modelos Moleculares , Estructura Molecular , Rodanina/síntesis química , Rodanina/química , Ribonucleósidos/química , Relación Estructura-ActividadRESUMEN
N- and S-galactosylation was carried out via the reaction of 5-((Z)-arylidene)-2-thioxo-4-thiazolidinones with 2,3,4,6-tetra-O-acetyl-α-d-galactopyranosyl bromide under alkaline conditions or under silylation conditions. Deacetylation of the N-galactosylation products was performed with concentrated hydrochloric acid in methanol (3.5%) or sodium methoxide in methanol without cleavage of the 2-thioxo-4-thaizolidinone ring by means of acid hydrolysis. The anomers were separated by flash column chromatography, and their configurations were assigned by NMR spectroscopy. The deprotected nucleosides were screened against leukemia L-1210 and were found inactive.
Asunto(s)
Galactosa/química , Tiazolidinedionas/síntesis química , Estructura Molecular , Estereoisomerismo , Tiazolidinedionas/químicaRESUMEN
New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Modelos Moleculares , Proteínas Supresoras de Tumor/metabolismo , Acetilación/efectos de los fármacos , Benzofuranos/química , Benzofuranos/metabolismo , Cadherinas/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with beta-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores Enzimáticos/farmacología , Glucurónidos/farmacología , Inhibidores de Histona Desacetilasas , Neoplasias Pulmonares/tratamiento farmacológico , Fenilendiaminas/farmacología , Profármacos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Benzamidas , Cadherinas/genética , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucurónidos/síntesis química , Glucurónidos/química , Humanos , Hidrólisis , Estructura Molecular , Fenilendiaminas/síntesis química , Fenilendiaminas/química , Profármacos/síntesis química , Profármacos/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
A variety of alkynylated amines, amides, and imides are reacted in the superacid system HF-SbF5 to give regioselectively new beta-gem-difluoroamines. The reaction, which is not observed in pure HF, is consistent with the formation of a dicationic intermediate (i.e., both vinylic and adjacent protonated N-ammonium cations). Application to the regioselective and efficient synthesis of difluorinated cinchona alkaloid derivatives is described.
Asunto(s)
Alquinos/química , Antimonio/química , Alcaloides de Cinchona/síntesis química , Fluoruros/química , Hidrocarburos Fluorados/síntesis química , Ácido Fluorhídrico/química , Amidas/química , Aminas/química , Cationes/química , Alcaloides de Cinchona/química , Cristalografía por Rayos X , Halogenación , Hidrocarburos Fluorados/química , Imidas/química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
New compounds derived from inhibitors of histone deacetylases (HDACs) have been synthesized and their antiproliferative activities towards non small lung cancer cell line H661 evaluated. Their design is based on hybrids between indanones to limit conformational mobility and other known HDAC inhibitors (SAHA, MS-275). The synthesis of these new derivatives was achieved by alkylation of appropriate indanones to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. These new analogues were found to be moderately active to inhibit H661 cell proliferation.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/farmacología , Indanos/farmacología , Piridinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Benzamidas/química , Benzamidas/metabolismo , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/metabolismo , Indanos/síntesis química , Indanos/metabolismo , Estructura Molecular , Piridinas/química , Piridinas/metabolismo , Relación Estructura-Actividad , VorinostatRESUMEN
New histone deacetylase inhibitors have been synthesized and evaluated for their activity against non-small lung cancer cell line H661. These compounds have been designed with diversely substituted 1,4-benzodiazepine-2,5-dione moieties as cyclic peptide mimic cap structures, and a hydroxamate side chain. Biological evaluations demonstrated that benzodiazepine-based HDACi bearing an aromatic substituent at the N1 position exhibited promising antiproliferative and HDAC-inhibitory activities.
Asunto(s)
Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Antineoplásicos/química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Línea Celular Tumoral , Química Farmacéutica/métodos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Histona Desacetilasas/química , Histonas/química , Humanos , Modelos Químicos , Conformación Molecular , Conformación Proteica , Tubulina (Proteína)/químicaRESUMEN
The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.
Asunto(s)
Fluoroacetatos , Ácidos Hidroxámicos/química , Acetamidas , Conformación de Carbohidratos , Glicosilación , Estructura Molecular , Ácido Trifluoroacético/químicaRESUMEN
Click chemistry has became an important tool for molecular constructs such as biopolymers. During the development of biodegradable multifunctional poly(ethylene oxide) (PEO) polymers suitable for click chemistry in water, an unexpected reaction leading to a mixture of triazole cycloadducts was observed. This result was attributed to an intramolecular ligand effect, and alternative conditions were evaluated. An efficient method was then implemented allowing the access in high yields to the expected triazolylcarbamate. pH sensitivity of the obtained isopropyltriazolylcarbamate was demonstrated at acidic pH.
RESUMEN
The beta-O-glucuronide and beta-O-galactoside of SAHA have been prepared and evaluated as prodrugs for selective cancer chemotherapy (ADEPT, PMT). These new compounds are stable under physiological conditions and do not exhibit any antiproliferative activity compared to the parent drug after a 48-h treatment of H661 cells. The glucuronide derivative did not lead to the release of the drug in the presence of either Escherichia coli or bovine liver beta-glucuronidase. On the other hand, under enzymatic cleavage of galactoside prodrug by the corresponding enzyme, a rapid release of SAHA was observed demonstrating that the beta-O-galactoside of SAHA is a promising candidate for in vivo investigations.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Ensayos Clínicos como Asunto , Galactósidos/síntesis química , Galactósidos/farmacología , Glucurónidos/síntesis química , Glucurónidos/farmacología , Humanos , Hidrólisis , VorinostatRESUMEN
New inhibitors of histone deacetylase (HDAC) have been synthesized and evaluated for their activity toward non small lung cancer cell line H661. Their design is based on indanone (or tetralone) systems leading to trichostatin A (TSA) analogs with limited conformational mobility. Molecular modelization at the AM1 level revealed that the conformations of indane-based analogs and TSA bound to HDAC like protein are similar. The synthesis of these new analogs was achieved by alkylation of an appropriate indanone (or tetralone) to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. Hydroxamic acids with the TSA side chain were found to be the most active compounds and the presence of the dimethylamino group on the phenyl ring turned out to be essential to achieve low micromolar activities against H661 cancer cells.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Ácidos Hidroxámicos/química , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis, enzymatic hydrolysis and self decomposition of model glucuronylated prodrugs, incorporating a new linker with different aryl substituents, have been studied. Determination of kinetic parameters (V(max), K(m) and t(1/2)) showed the important role of aromatic substitution in enzymatic recognition and linker decomposition.
Asunto(s)
Glucuronatos/química , Profármacos/química , Alcoholes/química , Carbamatos/síntesis química , Carbamatos/química , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli , Felbamato , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/metabolismo , Hidrólisis/efectos de los fármacos , Cinética , Estructura Molecular , Fenilcarbamatos , Profármacos/síntesis química , Profármacos/farmacología , Glicoles de Propileno/química , Glicoles de Propileno/metabolismoRESUMEN
A modified nitrogen and sulfur glycosylation reaction involving benzothiazole benzoxazole and pyridine nucleoside bases with furanose and pyranose sugars are described. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (2D DFQ-COSY, HMQC and HMBC). The N and S sites of glycosylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All the deprotected nucleosides were tested for their potential antitumor activity.
Asunto(s)
Antineoplásicos/síntesis química , Benzoxazoles/química , Nucleósidos/síntesis química , Piridinas/química , Tiazoles/química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzotiazoles , Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Línea Celular Tumoral , Humanos , Nucleósidos/química , Nucleósidos/farmacología , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
[reaction: see text]. (-)-PF1163B, a new macrocyclic antifungal antibiotic isolated from Streptomyces sp., has been prepared in eight steps from (S)-citronellene. The key step is a ring-closing metathesis reaction of an ester and amide derivative obtained from a substituted N-methyl-l-tyrosine.
Asunto(s)
Antifúngicos/síntesis química , Conformación Molecular , Antifúngicos/química , Ciclización , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Macrocíclicos , Espectroscopía de Resonancia Magnética , Metiltirosinas/química , Estructura Molecular , Monoterpenos/química , EstereoisomerismoRESUMEN
Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemann's ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di-O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained. Evaluation of their cytotoxicity against L1210 leukemia cells are reported.