RESUMEN
The heterocyclic compounds have a great importance in medicinal chemistry. One of the most important heterocycles in medicinal chemistry are quinazolines possessing wide spectrum of biological properties like antibacterial, antifungal, anticonvulsant, anti-inflammatory, anti-HIV, anticancer and analgesic activities. This skeleton is an important pharmacophore considered as a privileged structure. This review highlights the recent advances in the synthesis of quinazolines and quinazolinone derivatives with potent antimicrobial and cytotoxic activities.
RESUMEN
The relationships between the structural and energetic domains of lentil seedling amine oxidase (LSAO) were investigated using modifiers that target the active site and the carbohydrate moiety of the enzyme. An irreversible inhibitor, aminoguanidine, specifically modified the active site of the lentil enzyme, whereas sodium metaperiodate cleaves carbohydrate moieties covalently bound to the native enzyme. Differential scanning calorimetry (DSC) measurements were made on the modified LSAOs. Deconvolution of the reversible thermal DSC profiles of the modified enzyme gave three subpeaks (energetic domains), each of which was assigned to one of the three structural domains of the native protein. Our results led us to conclude that deglycosylation of LSAO has no effect on thermal stability, whereas binding of the inhibitor imparts more stability to the enzyme.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/química , Lens (Planta)/enzimología , Plantones/enzimología , Rastreo Diferencial de Calorimetría , Desnaturalización Proteica , Estructura Terciaria de ProteínaRESUMEN
Syntheses of racemic trans-3-hydroxycarbonyl-6-(phenylacetamido)carbapenem (13), trans-3-phosphono-6-(phenylacetamido)carbapenem (17), and beta-lactam based prodrugs 19 and 22 were accomplished. Carbapenem 13 was found to possess antibacterial activity, comparable with imipenem (+)-3, against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiella pneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, P. aeruginosa 18S-H, and Xanthomonas maltophilia GN 12873. Like imipenem ((+)-3), carbapenem 13 was not stable to X. maltophilia oxyiminocephalosporinase type II. Its phosphonate analog 17, however, was neither a significant antibacterial agent nor a good beta-lactamase inhibitor. Chemical combinations of trans carbapenem 13 with cis carbapenem 6 (compound 19) as well as clavulanic acid (20) with cis carbapenem 6 (compound 22) via a tetrachloroethane linker exhibited remarkable activity against beta-lactamase producing microorganisms in vitro.
Asunto(s)
Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Diseño de Fármacos , Profármacos/síntesis química , Profármacos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Carbapenémicos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Profármacos/química , Inhibidores de beta-Lactamasas , beta-Lactamasas/metabolismoRESUMEN
Thermodynamic studies were carried out to evaluate the binding of theophylline on adenosine deaminase (ADA) in 50 mM sodium phosphate buffer pH 7.5, at 300 K, using isothermal titration calorimetry (ITC). A simple method for determination of binding isotherm in the drug--ADA interaction was applied using ITC data. ADA has two binding sites for theophylline, which show positive cooperativity in its sites. The intrinsic association equilibrium constants are 6 and 52 mM(-1) in the first and second binding sites, respectively. Hence, occupation of the first site has produced an appreciable enhancement by 8.7 of the binding affinity of the second site. The molar enthalpies of binding are -12.2 and -14.9 kJ/mol in the first and second binding sites, respectively.
Asunto(s)
Adenosina Desaminasa/química , Broncodilatadores/química , Inhibidores de Fosfodiesterasa/química , Teofilina/química , Calorimetría , Ligandos , Unión Proteica , Termodinámica , VolumetríaRESUMEN
Different types of cardiotoxin (I-V and n) were isolated and purified from the venom of the Taiwan cobra (Naja naja atra). The effects of these cardiotoxins were studied on membrane-bound acetylcholinesterase, which was isolated from a sheep's brain cortex. The results showed that cardiotoxins I-III, V, and n activated the enzyme by modification of substrate inhibition, but cardiotoxin IV's reaction was different. The inhibition and activation of acetylcholinesterase were linked to the functions of the hydrophobicity index, presence of a cationic cluster, and the accessible arginine residue. Our results indicate that Cardiotoxins have neither a cationic cluster nor an arginine residue in their surface area of loop I; therefore, in contrast to fasciculin, cardiotoxins are attached by loop II to the peripheral site of the enzyme. As a result, fasciculin seems to stabilize nonfunctional conformation, but cardiotoxins seem to stabilize the functional conformation of the enzyme. Based on our experimental and theoretical findings, similar secondary and tertiary structures of cardiotoxins and fasciculin seem to have an opposite function once they interact with acetylcholinesterase.
Asunto(s)
Acetilcolinesterasa/metabolismo , Proteínas Cardiotóxicas de Elápidos/metabolismo , Sinaptosomas/enzimología , Acetilcolinesterasa/química , Secuencia de Aminoácidos , Animales , Química Encefálica , Corteza Cerebral/enzimología , Proteínas Cardiotóxicas de Elápidos/química , Proteínas Cardiotóxicas de Elápidos/genética , Venenos Elapídicos/química , Venenos Elapídicos/genética , Venenos Elapídicos/metabolismo , Elapidae , Activación Enzimática , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Alineación de Secuencia , OvinosRESUMEN
The absence of effective vaccines for most viral infections highlights an urgent necessity for the design and development of effective antiviral drugs. Due to the advancement in virology since the late 1980s, several key events in the viral life cycle have been well delineated and a number of molecular targets have been validated, culminating in the emergence of many new antiviral drugs in recent years. Inhibitors against enteroviruses and rhinoviruses, responsible for about half of the human common colds, are currently under active investigation. Agents targeted at either viral protein 1 (VP1), a relatively conserved capsid structure mediating viral adsorption/uncoating process, or 3C protease, which is highly conserved among different serotypes and essential for viral replication, are of great potential to become antipicornavirus drugs.
Asunto(s)
Antivirales/farmacología , Cápside/metabolismo , Enterovirus/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Rhinovirus/efectos de los fármacos , Antivirales/metabolismo , Inhibidores de Proteasas/metabolismo , Unión ProteicaRESUMEN
Racemic 7-(phenylacetamido)-1-dethia-3-aza-1-carba-2-oxacephem 3 was synthesized and found to possess antibacterial activity against Staphylococcus aureus FDA 209P, Escherichia coli ATCC 39188, Pseudomonas aeruginosa 1101-75 and Klebsiella pneumoniae NCTC 418 as well as the beta-lactamase producing organisms E. coli A9675 and P. aeruginosa 18S-H and the methicillin-resistant organism S. aureus 95. Formation of the carbacephem 3 originated from the Barton photochemical reaction in the conversion of 8 to 10. Intramolecular cyclization of syn-oximino beta-lactam 10 afforded 7-azido-2-oxa-3-azacephem 11, which was reduced and acylated to 12. Enzymatic removal of the methyl group from 12 gave the target molecule 3.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Escherichia coli/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/química , División Celular/efectos de los fármacos , Células Cultivadas , Cefalosporinas/química , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/química , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Escherichia coli/genética , Humanos , Isomerismo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/genética , Staphylococcus aureus/enzimología , Staphylococcus aureus/genética , Inhibidores de beta-Lactamasas , beta-Lactamas/química , beta-Lactamas/farmacologíaRESUMEN
Synthesis of adenine derivative of triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 4 was accomplished by treatment of phosphonate 3 with 5-phosphoribosyl 1-pyrophosphate in the presence of 5-phosphoribosyl 1-pyrophosphate synthetase. It was found that triphosphonate 4 functions as an irreversible stoichiometric inactivator of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). Triphosphonate 4 exhibited potent inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. Paclitaxel ester derivatives of adenine-containing triphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 8-10 were also synthesized. Like triphosphonate 4, compound 8 exhibited inhibitory property toward RDPR. It also induced microtubule assembly similar to paclitaxel (5). The structure of the chlorodiester linker in 8 was found to account for this dual property. After treatment of MCF7 cells with compounds 4, 5, and 8, fluorescence microscope examination demonstrated the presence of nucleus shrinkage or segmentation. Bifunctional prodrug 8 exhibited higher lipophilicity than 4 and higher water-solubility than 5. Pro-dual-drug 8 exhibited more pronounced anticancer activity relative to that of the triphosphonate 4 and paclitaxel (5). In contrast, compound 9, resulting from the linkage of triphosphonate 4 and paclitaxel (5) through a diester unit, was only found to function as a highly water-soluble prodrug for paclitaxel (5). It induced microtubule assembly in vitro, but did not show inhibitory property toward RDPR. On the other hand, compound 10, an aggregate of triphosphonate 4 and paclitaxel (5), neither functioned as an inhibitor of RDPR nor exhibited microtubule assembly stimulating activity in vitro.
Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/síntesis química , Diseño de Fármacos , Paclitaxel/análogos & derivados , 4-Butirolactona/análogos & derivados , Adenina/síntesis química , Adenina/farmacología , Animales , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Difosfatos/química , Ensayos de Selección de Medicamentos Antitumorales , Furanos/química , Humanos , Microtúbulos/efectos de los fármacos , Organofosfonatos/química , Paclitaxel/química , Paclitaxel/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Solubilidad , Relación Estructura-ActividadRESUMEN
By use of pro-dual-drug concept the synthesis of 6-beta-[(R)-2-(clavaminio-9-N-yl)-2-(4-hydroxyphenylacetamido)]penicillanic acid (10), 6-beta-[(R)-2-(amino)-2-(4-(clavulano-9-O-yl)phenylacetamido)]penicillanic acid (13), (Z)-4-[2-(amoxycillin-4-O-yl)ethylidene]-2-(clavulano-9-O-yl)-3-methoxy-Delta(alpha,beta)-butenolide (19), and 3-[(amoxicillin-4-O-yl)methyl]-7-(phenoxyacetamido)-(1-oxo)-3-cephem-4-carboxylic acid (23) was accomplished. Unlike penicillin G, ampicillin, or amoxicillin, these four heretofore undescribed compounds 10, 13, 19, and 23 showed notable activity against beta-lactamase (betaL) producing microorganisms, Staphylococcus aureus A9606, S. aureus A15091, S. aureus A20309, S. aureus 95, Escherichia coli A9675, E. coli A21223, E. coli 27C7, Pseudomonas aeruginosa 18S-H, and Klebsiella pneumoniae A20634 TEM. In comparison with amoxicillin (9), alpha-amino-substituted compound 10 and butenolide derivative 19 showed a broadened spectrum of antibacterial activity; yet they were found to be less active than 13 and 23. Like clavulanic acid (7) or cephalosporin-1-oxide (21), the newly synthesized compounds 10, 13, 15, 16, 19, or 23 functioned as potent inhibitors of various bacterial betaLs.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Profármacos/síntesis química , Profármacos/farmacología , Amoxicilina/análogos & derivados , Amoxicilina/síntesis química , Amoxicilina/farmacología , Antibacterianos/química , Tampones (Química) , Fenómenos Químicos , Química Física , Ácido Clavulánico/síntesis química , Ácido Clavulánico/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hidrólisis , Lípidos/química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Solubilidad , Relación Estructura-Actividad , Inhibidores de beta-LactamasasRESUMEN
A novel cephalosporin derivative of monohydroguaiaretic acid (cephem-M(3)N, 7) was synthesized and found to possess anticancer activity against human leukemia (K562), breast carcinoma (MCF7), human lung cancer (A549), human colon cancer (Colo205) and pancreatic cancer cells (Capan2 and MiaPaCa2). A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based M(3)N 7 and its potency toward K562, MCF7, A549, Colo205, Capan2, and MiaPaCa2 was found to approach that of the free M(3)N (4). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to conjugate 7 than normal human embryonic lung (HEL) cells and normal fibroblasts (Hef522). These notions provide a new approach to the use of nordihydroguaiaretic acid (NDGA) and its derivatives for antitumor therapy.
Asunto(s)
Antineoplásicos/síntesis química , Inmunoconjugados/farmacología , Profármacos/síntesis química , beta-Lactamasas/farmacología , Anticuerpos Antineoplásicos , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Cefalosporinas , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Hidrólisis/efectos de los fármacos , Inmunoconjugados/metabolismo , Masoprocol , Profármacos/metabolismo , Profármacos/farmacología , Células Tumorales Cultivadas , beta-Lactamasas/inmunología , beta-Lactamasas/metabolismoRESUMEN
Thiols are the most reactive nucleophilic reagents among the biological models investigated. The reactivity of butenolides 1a-c, 2-4, and 6-8 toward L-cysteine, a model biological nucleophile, was studied spectrophotometrically. The rates of the reactions were measured and correlated with antitumour activity of these molecules. N-Acetylcysteine addition product 5, resulting from the treatment of butenolide 4 with glutathione precursor, N-acetyl-L-cysteine, was isolated. Unlike purine-containing gamma-(Z)-ethylidene-2,3-dimethoxybutenolides 1a-c, 4, 6, and 7, adduct 5 and butenolides 10-12 did not exhibit inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. As such, the biological activity of purine-containing butenolides can be attributed to their adenine moiety as a recognition site as well as their reactivity towards the cysteine residues of functional proteins forming covalent bond via reverse Michael type addition. Adenine-containing phosphonothioanhydride derivative 8 was also synthesised. Its reaction with N-acetyl-L-cysteine produced N,S-diacetylcysteine and thiophosphonate 9. Compound 9 did not exhibit anticancer activity; yet its precursor 8 displayed the most pronounced inhibition on all the examined malignant tumour cell lines. In the presence of L-cysteine, cytotoxicity of 4 and 8 was decreased, whereas glutathione addition more influenced on the cytotoxicity of 8. It was found that adenine-containing phosphonothioanhydride 8 functions as a significant irreversible inactivator of the Escherichia coli ribonucleoside diphosphate reductase. After treatment of MCF7 cells with compound 8, fluorescence microscopy demonstrated the presence of nucleus shrinkage or segmentation. This apoptotic morphology, however, was not pronounced in the presence of glutathione or dithiotheritol.
Asunto(s)
Acetilcisteína/química , Apoptosis/efectos de los fármacos , Cisteína/química , Furanos/química , Furanos/farmacología , Purinas/química , Ribonucleótido Reductasas/antagonistas & inhibidores , 4-Butirolactona/análogos & derivados , Acetilcisteína/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular , Cisteína/farmacología , Citarabina/toxicidad , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Fibroblastos , Furanos/toxicidad , Humanos , Ratones , Estructura Molecular , Ribonucleótido Reductasas/metabolismo , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Células Tumorales CultivadasRESUMEN
A novel uracil-containing enediyne was synthesized by the fusion at N(1) and N(3) of uracil with an 11-membered cyclic enediyne. Compound was found to be stable against cycloaromatization at 80 degreesC. Thus, it did not cause DNA-damage. Unlike other alkylated uracil derivatives 2--6, highly strained uracil-containing enediyne was reacted with methyl thioglycolate at 25 degreesC to produce uracil () and linear enediyne. This reactivity toward a sulfhydryl group may play a significant role in the mechanism by which compound directed its cytotoxicity toward tumor cell lines. Tumor cells were found to be more susceptible to enediyne than normal human embryonic lung cells. A combination of with adriamycin or 1-(beta-D-arabinofuranosyl)cytosine resulted in synergistic anticancer activity against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF--CEM lymphoblastic leukemia. After treatment of Molt-4 cells with uracil-containing enediyne, light microscope examination demonstrated the presence of cell shrinkage and nuclear segmentation. Treatment of cultured Molt-4 human leukemia cells with enediyne resulted in a time-dependent depletion of glutathione (GSH) whereas the exposure of the cells to the GSH precursor N-acetylcysteine (NAC) resulted in a substantial suppression of this effect. As such, involvement of GSH depletion in the process of apoptosis may explain the mechanism of action of non-genotoxic enediyne against malignant tumor cell lines.