RESUMEN
Schizophrenia and depression are diseases that significantly impede human functioning in society. Current antidepressant drugs are not fully effective. According to literature data, the effect on D2R or 5-HT1AR can effectively reduce the symptoms of depression or schizophrenia. Recent research hypothetized that the synergism of both of these receptors can improve the effectiveness of therapy. Ipsapirone, a representative of long-chain arylpiperazines, is a known 5-HT1AR ligand that has antidepressant effect. This compound has no affinity for the D2R. Bearing in mind, we decided to design ligands with improved affinity to D2R and confirmed that in some cases elongation of the carbon linker or arylpiperazine exchange may have beneficial influence on the binding to D2R and 5-HT1AR. Four groups of ligands being ipsapirone analogues with butyl, pentyl, hexyl and stiffened xylene chains were designed. All compounds were obtained in solvent-free reactions supported by a microwave irradiation with an efficiency mainly above 60%. All ligands containing 1-(2-pyrimidinyl)piperazine exhibited high affinity to 5-HT1AR. In this case, chemical modifications within the chain did not affect the affinity to D2R. In the case of ligands containing 1-phenylpiperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(1-naphthyl)piperazine, and 1-(4-chlorophenyl)piperazine, elongation of carbon linker increases of affinity to D2R. For ligands containing 1- (2-pyridyl) piperazine, and 1-(2,3-dichlorophenyl)piperazine, we observed an opposite effect. For ligands containing 1-phenylpiperazine, 1-(2-methoxyphenyl)piperazine and 1-(2-pyridyl)piperazine, chain elongation had no effect on 5-HT1AR binding. In turn of ligands containing 1-(3-trifluoromethylphenyl)piperazine and 1- (2,3-dichlorophenyl)piperazine, we observed that elongation of carbon linker has a positive influence to 5-HT1AR. Molecular modelling was used to support the SAR study.
Asunto(s)
Antidepresivos/farmacología , Pirimidinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Sacarina/farmacología , Antidepresivos/síntesis química , Antidepresivos/química , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Pirimidinas/química , Sacarina/síntesis química , Relación Estructura-ActividadRESUMEN
A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/síntesis química , Anhidrasas Carbónicas/metabolismo , Sacarina/síntesis química , Edulcorantes/síntesis química , Tiazinas/síntesis química , Inhibidores de Anhidrasa Carbónica/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Sacarina/metabolismo , Sacarina/farmacología , Relación Estructura-Actividad , Edulcorantes/metabolismo , Edulcorantes/farmacología , Tiazinas/metabolismo , Tiazinas/farmacología , Triazoles/química , Zinc/químicaRESUMEN
Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Sacarina/química , Sacarina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/síntesis química , Línea Celular , Reacción de Cicloadición , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Isoxazoles/farmacología , Células MCF-7 , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/metabolismo , Sacarina/síntesis químicaRESUMEN
Allylation and conjunctive cross-coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer exciting possibilities in organic synthesis but remains largely unknown. Herein, we report the use of allyl electrophiles in nickel-catalyzed conjunctive cross-coupling with a non-conjugated alkene and dimethylzinc. The transformation is enabled by weakly coordinating, monodentate aza-heterocycle directing groups that are useful building blocks in synthesis, including saccharin, pyridones, pyrazoles, and triazoles. The reaction occurs under mild conditions and is compatible with a wide range of allyl electrophiles. High chemoselectivity through substrate directivity is demonstrated by the facile reactivity of the ß-γ alkene of the starting material, whereas the ϵ-ζ alkene of the product is preserved. The generality of this approach is further illustrated through the development of an analogous method with alkyne substrates. Mechanistic studies reveal the importance of the dissociation of the weakly coordinating directing group to allow the allyl moiety to bind and facilitate C(sp3 )-C(sp3 ) reductive elimination.
Asunto(s)
Compuestos Alílicos/química , Níquel/química , Pirazoles/síntesis química , Piridonas/síntesis química , Sacarina/síntesis química , Triazoles/síntesis química , Alquenos/química , Alquilación , Catálisis , Estructura Molecular , Compuestos Organometálicos/química , Pirazoles/química , Piridonas/química , Sacarina/química , Estereoisomerismo , Triazoles/químicaRESUMEN
The sweeteners saccharin (SAC) and acesulfame K (ACE) recently entered the topic of anticancer human carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, as they showed to selectively inhibit the tumor-associated CAs IX/XII over ubiquitous CAs. A drug design strategy is here reported, which took SAC and ACE as leads and produced a series of 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one-1,1-dioxides (BTD). Many derivatives showed greater potency (KIs-CA IX 19.1-408.5 nM) and selectivity (II/IX SI 2-76) than the leads (KIs-CA IX 103, 2400 nM; II/IX-SI 56, >4) against CA IX/XII over off-target isoforms. A thorough X-ray crystallographic study depicted their binding mode to both CA II and IX-mimic. The most representative BTDs were characterized in vitro for their antitumor activity against A549, PC-3, and HCT-116 cancer cell lines both in normoxia and hypoxia. The two most effective compounds were assayed for their effect on several apoptosis markers, identifying promising leads for the development of new anticancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Sacarina/análogos & derivados , Sacarina/farmacología , Sulfonamidas/farmacología , Tiazinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Pruebas de Enzimas , Humanos , Estructura Molecular , Sacarina/síntesis química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Tiazinas/síntesis química , Tiazinas/químicaRESUMEN
A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen.
Asunto(s)
Acetaminofén/análogos & derivados , Antipiréticos/química , Antipiréticos/uso terapéutico , Fiebre/tratamiento farmacológico , Sacarina/análogos & derivados , Acetaminofén/síntesis química , Acetaminofén/química , Acetaminofén/uso terapéutico , Acetaminofén/toxicidad , Animales , Antipiréticos/síntesis química , Antipiréticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cristalografía por Rayos X , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Esterificación , Fiebre/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Modelos Moleculares , Nitratos/síntesis química , Nitratos/química , Nitratos/uso terapéutico , Nitratos/toxicidad , Ratas , Sacarina/síntesis química , Sacarina/química , Sacarina/uso terapéutico , Sacarina/toxicidadRESUMEN
Among the potential applications of coordination polymers, electrical conductivity ranks high in technological interest. We report the synthesis, crystal structure and spectroscopic analysis of an AgI-thiosaccharinate one-dimensional coordination polymer {systematic name: catena-poly[[[aquatetrakis(µ3-1,1-dioxo-1,2-benzisothiazole-3-thiolato-κ3N:S3:S3)tetrasilver(I)]-µ2-4,4'-(propane-1,3-diyl)dipyridine-κ2N:N'] dimethyl sulfoxide hemisolvate]}, {[Ag4(C7H4NO2S2)4(C13H14N2)(H2O)]·0.5C2H6OS}n, with the 4,4'-(propane-1,3-diyl)dipyridine ligand acting as a spacer. A relevant feature of the structure is the presence of an unusually short Ag...Ag distance of 2.8306â (9)â Å, well within the range of argentophilic interactions, confirmed experimentally as such by a Raman study on the low-frequency spectrum, and corroborated theoretically by an Atoms in Molecules (AIM) analysis of the calculated electron density. Electrical conductivity measurements show that this complex can act as a semiconductor with moderate conductivity.
Asunto(s)
Complejos de Coordinación/química , Polímeros/química , Sacarina/análogos & derivados , Sacarina/química , Plata/química , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Conductividad Eléctrica , Ligandos , Modelos Químicos , Estructura Molecular , Polímeros/síntesis química , Teoría Cuántica , Sacarina/síntesis químicaRESUMEN
Reports showing that the copper concentration is considerably higher in neoplasms than in normal tissues prompted the need to develop selective copper chelators. We disclosed recently that some N-linked tetrazole-saccharinates bind selectively to copper, forming complexes that are highly cytotoxic towards cancer cells. Because tetrazole-saccharinates are photolabile, due to the photoreactivity of tetrazoles, we proposed thiadiazolyl-saccharinates as an alternative. Herein we describe the synthesis, structure, and monomeric photochemistry of a sulphanyl-bridged thiadiazolyl-saccharinate, 3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulphanyl]-1,2-benzothiazole 1,1-dioxide (MTSB). The monomeric structure, charge density analysis, and characteristic infrared spectrum of MTSB were investigated theoretically, using quantum chemical calculations, and also experimentally, using matrix-isolation infrared spectroscopy. The crystal structure was investigated by combining X-ray crystallography with infrared and Raman spectroscopies. Results show that the structure of isolated MTSB is similar to that found in the crystal, with an Sâ â â N interaction clearly contributing to the structure of the molecule and of the crystal. Matrix irradiation revealed a high photostability of MTSB, compared to parent tetrazole-saccharinates and to the 5-methyl-1,3,4-thiadiazole building block, emphasizing the photostabilizing effect of the saccharyl system. Finally, in vitro toxicity assays of MTSB showed a copper concentration-dependent toxicity against cancer cells, without affecting normal cells. In particular, MTSB was most effective towards the hepatic (HepG2), neuroblastoma (SH-SY5), and lymphoma cell lines (U937). Thus, MTSB represents a promising lead for cancer chemotherapy based on chelating agents.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Sacarina/análogos & derivados , Sacarina/síntesis química , Sacarina/farmacología , Compuestos de Azufre/síntesis química , Compuestos de Azufre/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Antineoplásicos/química , Benzotiazoles/química , Compuestos Heterocíclicos de Anillo en Puente/química , Humanos , Estructura Molecular , Sacarina/química , Relación Estructura-Actividad , Compuestos de Azufre/química , Tiadiazoles/químicaRESUMEN
The salts 3-[(2,2,3,3-tetrafluoropropoxy)methyl]pyridinium saccharinate, C9H10F4NO+·C7H4NO3S-, (1), and 3-[(2,2,3,3,3-pentafluoropropoxy)methyl]pyridinium saccharinate, C9H9F5NO+·C7H4NO3S-, (2), i.e. saccharinate (or 1,1-dioxo-1λ6,2-benzothiazol-3-olate) salts of pyridinium with -CH2OCH2CF2CF2H and -CH2OCH2CF2CF3 meta substituents, respectively, were investigated crystallographically in order to compare their fluorine-related weak interactions in the solid state. Both salts demonstrate a stable synthon formed by the pyridinium cation and the saccharinate anion, in which a seven-membered ring reveals a double hydrogen-bonding pattern. The twist between the pyridinium plane and the saccharinate plane in (2) is 21.26â (8)° and that in (1) is 8.03â (6)°. Both salts also show stacks of alternating cation-anion π-interactions. The layer distances, calculated from the centroid of the saccharinate plane to the neighbouring pyridinium planes, above and below, are 3.406â (2) and 3.517â (2)â Å in (1), and 3.409â (3) and 3.458â (3)â Å in (2).
Asunto(s)
Compuestos de Piridinio/química , Sacarina/química , Cristalografía por Rayos X , Hidrocarburos Fluorados/química , Enlace de Hidrógeno , Estructura Molecular , Compuestos de Piridinio/síntesis química , Sacarina/síntesis químicaRESUMEN
A series of N-substituted saccharins incorporating aryl, alkyl and alkynyl moieties, as well as some ring opened derivatives were prepared and investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The widespread cytosolic isoforms CA I and II were not inhibited by these sulfonamides whereas transmembrane, tumor-associated ones were effectively inhibited, with KIs in the range of 22.1-481nM for CA IX and of 3.9-245nM for hCA XII. Although the inhibition mechanism of these tertiary/secondary sulfonamides is unknown for the moment, the good efficacy and especially selectivity for the inhibition of the tumor-associated over the cytosolic, widespread isoforms, make these derivatives of considerable interest as enzyme inhibitors with various pharmacologic applications.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Sacarina/farmacología , Antígenos de Neoplasias/metabolismo , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Sacarina/síntesis química , Sacarina/química , Relación Estructura-ActividadRESUMEN
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, ß-secretase and ß-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 µM to 19.18 µM. The target compounds displayed inhibition of human ß-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 µM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 µM) and inhibitory activity against hBACE1 (33.61% at 50 µM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 µM) with BACE1 inhibitory activity (26.3% at 50 µM) and it displays the most significant Aß anti-aggregating properties among all the obtained compounds (39% at 10 µM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
Asunto(s)
Aminas/química , Aminas/farmacología , Ftalimidas/química , Ftalimidas/farmacología , Sacarina/química , Sacarina/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Colinesterasas/metabolismo , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Ftalimidas/síntesis química , Agregación Patológica de Proteínas , Unión Proteica/efectos de los fármacos , Sacarina/síntesis químicaRESUMEN
A rhodium-catalyzed C-H functionalization with activated amides by decarbonylation has been developed. Notably, this is the first C-H arylation employing N-acylsaccharins as coupling partners to give biaryls in good to excellent yields. The highlight of the work is the high tolerance of functional groups such as formyl, ester, and vinyl and the use of a removable directing group.
Asunto(s)
Amidas/química , Rodio/química , Sacarina/síntesis química , Catálisis , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Sacarina/químicaRESUMEN
We report the development of a novel series of saccharin-based N-hydroxybenzamides as histone deacetylases inhibitors. Among them, 6 j exhibited potent HDACs inhibitory activity against Hela nuclear extract. Further biological evaluation found 6 i showed similar antiproliferative activities in vitro compared with the approved SAHA.
Asunto(s)
Benzamidas/química , Benzamidas/síntesis química , Inhibidores de Histona Desacetilasas/síntesis química , Sacarina/química , Sacarina/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Highly stereoselective synthesis of saccharin derivatives containing functionalized 2-azetidinone moiety was achieved starting from saccharin as an available precursor. The approach to these valuable heterocyclic scaffolds involves a formal [2π + 2π] cycloaddition between Schiff bases and the saccharinylketene as a novel ketene which was generated in situ and an electrocyclic reaction of a zwitterionic intermediate. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TOâ¢). Also, the antimicrobial activities of some new substituted saccharin against nine standard bacteria, four bacteria which were isolated from clinical samples and one yeast, were evaluated.
Asunto(s)
Antibacterianos/síntesis química , Etilenos/química , Cetonas/química , Sacarina/síntesis química , beta-Lactamas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Reacción de Cicloadición , Estructura Molecular , Sacarina/química , Sacarina/farmacología , Bases de Schiff , Estereoisomerismo , beta-Lactamas/química , beta-Lactamas/farmacologíaRESUMEN
Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50 = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Bencilaminas/síntesis química , Bencilaminas/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Fragmentos de Péptidos/metabolismo , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/química , Sitios de Unión , Unión Competitiva , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/metabolismo , Permeabilidad Capilar , Dominio Catalítico , Inhibidores de la Colinesterasa/metabolismo , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/metabolismo , Cinética , Ligandos , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Fragmentos de Péptidos/química , Agregación Patológica de Proteínas , Unión Proteica , Conformación Proteica , Sacarina/análogos & derivados , Sacarina/síntesis química , Sacarina/farmacología , Relación Estructura-ActividadRESUMEN
Saccharin, uracil, and 1,2,4-oxadiazole heterocyles are important in terms of exhibiting various biological acitivities. In this work, four series of 1,2,4-oxadiazolylmethyl-substituted saccharin, and uracil derivatives are synthesized and their structures are identified by means of spectral/physical characteristics. The first series are oxadiazolylmethyl-substituted saccharins. The second one is oxadiazole-substituted uracils which are obtained as a separable mixture of both mono- and bis-substituted end products. Third series is obtained from 5-amino uracil and chloromethyl oxadiazoles. The fourth group is oxadiazolyl methyl-substituted imino uracils. The structures of some title compounds are also confirmed by X-ray diffraction data.
Asunto(s)
Estructura Molecular , Sacarina/análogos & derivados , Sacarina/síntesis química , Uracilo/análogos & derivados , Uracilo/síntesis química , Modelos Moleculares , Conformación MolecularRESUMEN
The new platinum(II) complexes cis-[Pt(sac)2(NH3)2] (sac=saccharinate) and cis-[Pt(tsac)2(NH3)2] (tsac=thiosaccharinate) have been prepared, the X-ray crystal structure of cis-[Pt(sac)2(NH3)2] x H2O reveals that both saccharinate anions are N-bound in a cis-arrangement being inequivalent in both the solid-state and in solution at room temperature. Preliminary anti-cancer activity has been assessed against A549 human alveolar type-II like cell lines with the thiosaccharinate complex showing good activity.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Compuestos Organoplatinos/síntesis química , Sacarina/síntesis química , Edulcorantes/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Humanos , Metotrexato/farmacología , Compuestos Organoplatinos/farmacología , Sacarina/análogos & derivados , Sacarina/farmacología , Relación Estructura-Actividad , Edulcorantes/farmacologíaRESUMEN
A new, electrophilic trifluoromethylthiolating reagent, N-trifluoromethylthiosaccharin, was developed and can be synthesized in two steps from saccharin within 30â minutes. N-trifluoromethylthiosaccharin is a powerful trifluoromethylthiolating reagent and allows the trifluoromethylthiolation of a variety of nucleophiles such as alcohols, amines, thiols, electron-rich arenes, aldehydes, ketones, acyclic ß-ketoesters, and alkynes under mild reaction conditions.
Asunto(s)
Sacarina/análogos & derivados , Compuestos de Sulfhidrilo/síntesis química , Estructura Molecular , Sacarina/síntesis química , Sacarina/química , Compuestos de Sulfhidrilo/químicaRESUMEN
A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with KIs ranging between 11 and 390 nM, whereas they were inactive against both CA I (KIs >50 µM) and II (K(I)s ranging between 39.1 nM and 50 µM). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Diseño de Fármacos , Sacarina/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Sacarina/síntesis química , Sacarina/química , Relación Estructura-ActividadRESUMEN
A newly series of 6-(phenylurenyl/thiourenyl) saccharin (6a-y) derivatives were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. A 70-fold purification of the enzyme with 6.85% yield was achieved by using a Sepharose 4B-l-tyrosine-p-amino benzoic acid affinity column. The result showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among the compounds synthesized, 6-(3-iodophenylthiourenyl) saccharin (6s) was found to be most active one (K(i)=3.95 µM) and the inhibition kinetics analyzed by Lineweaver-Burk double reciprocal plots revealed that compound 6s was a competitive inhibitor. Structure-activity relationships study showed that generally, most of the 6-(phenylthiourenyl) saccharin derivatives (6m-y) exhibited higher inhibitory activity than 6-(phenylurenyl) saccharin derivatives (6a-l). An electron-withdrawing group at 3-position of phenylurenyl-ring increased in activity and the halogen series at 3-position of phenylthiourenyl-ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. We also calculated HOMO-LUMO energy levels and dipole moments of some selected the synthesized compounds (6a, 6h, 6m and 6s) using Gaussian software.