RESUMO
New C-glycosides and α,ß-unsaturated ketones incorporating the 4-hydroxy-3-methoxyphenyl (vanillin) moiety as inhibitors of carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been investigated. The inhibition profile of these compounds is presented against four human CA (hCA) isozymes, comprising hCAs I and II (cytosolic, ubiquitous enzymes) and hCAs IX and XII (tumour associated isozymes). Docking analysis of the inhibitors within the active sites of these enzymes has been performed and is discussed, showing that the observed selectivity could be explained in terms of an alternative pocket out of the CA active site where some of these compounds may bind. Several derivatives were identified as selective inhibitors of the tumour-associated hCA IX and XII. Their discovery might be a step in the strategy for finding an effective non-sulfonamide CA inhibitor useful in therapy/diagnosis of hypoxic tumours or other pathologies in which CA isoforms are involved.
Assuntos
Benzaldeídos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Desenho de Fármacos , Antígenos de Neoplasias/metabolismo , Benzaldeídos/síntese química , Benzaldeídos/química , Sítios de Ligação/efeitos dos fármacos , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Attachment of different tails to the well-known carbonic anhydrase (CA) pharmacophores has led to the development of several new CA inhibitors (CAIs). A very good example of such "tails" is constituted by carbohydrates, which represent a wide range of chemotypes, leading thus to a high number of new CAIs. In the last years, several C-cinnamoyl glycosides containing different scaffolds have been prepared and investigated as carbonic anhydrase inhibitors, showing that some of them are very potent and selective CAIs. This article will review the latest developments in the synthesis and biological activity of these Cglycosides.
Assuntos
Butanonas/química , Inibidores da Anidrase Carbônica/química , Glicosídeos/química , Antituberculosos/síntese química , Antituberculosos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Butanonas/síntese química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Domínio Catalítico , Glicosídeos/síntese química , Humanos , Estrutura MolecularRESUMO
One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated 'the sugar approach'. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C-glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. The inhibition profile of the new glycomimetics was determined against four human (h) CA isozymes, comprising hCAs I and II (cytosolic, ubiquitous isozymes), hCA IV and hCA IX (tumor associated isozyme). Peracetylated and deprotected C-glycosyl sulfamates showed better inhibition selectivity compared to structurally related phenylsulfamates. In this study, deprotected compound 12 was identified as selective inhibitor of hCA IX. These results confirm that attaching carbohydrate moieties to CA sulfamoylphenyl pharmacophore improves its inhibitory activity.
Assuntos
Inibidores da Anidrase Carbônica/química , Glucosídeos/química , Sulfonamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/síntese química , Ensaios Enzimáticos , Glucosídeos/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Topiramato/químicaRESUMO
A small series of N-glycosylsulfonamides incorporating the phenol moiety has been prepared by Ferrier sulfonamidoglycosylation of d-glycals. N-Glycosides were tested for the inhibition of four isoforms of carbonic anhydrase. In this study, all compounds showed good inhibitory activity against hCA I and II, with selectivity against the cytosolic hCA II versus the tumor associated isozymes. These results confirm that attaching carbohydrate moieties to CA phenol pharmacophore improves and enhances its inhibitory activity.
Assuntos
Anidrase Carbônica II/metabolismo , Anidrase Carbônica I/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Fenóis/química , Sulfonamidas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
During the treatment of tuberculosis infection, oxidative stress due to anti-tubercular drugs may result in tissue inflammation. It was suggested that treatment with antioxidant drugs could be beneficial as an adjunct to anti-tuberculosis drug therapy. Recently our group has shown that several C-glycosides are inhibitors of Mycobacterium tuberculosis ß-carbonic anhydrases (CAs, EC 4.2.1.1). In an effort to develop novel chemotherapeutic agents against tuberculosis, the anti-tubercular and antioxidant activities of a series of C-glycosides containing the phenol or the methoxyaryl moiety were studied. Many compounds showed inhibition of growth of M. tuberculosis H37Rv strain and good antioxidant ability. A glycomimetic incorporating the 3-hydroxyphenyl moiety showed the best activity profile and therefore this functionality represents lead for the development of novel anti-tubercular agents with dual mechanisms of action.
Assuntos
Antioxidantes/farmacologia , Antituberculosos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
A small series of C-glycosides containing the phenol moiety was tested for the inhibition of the ß-class carbonic anhydrases (ßCAs, EC 4.2.1.1) from Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. Glycosides incorporating the 3-hydroxyphenyl moiety showed the best inhibition profile, and therefore this functionality represents lead for the development of novel anti-infectives with a new mechanism of action.
Assuntos
Brucella suis/enzimologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Glicosídeos/farmacologia , Fenóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Glicosídeos/química , Estrutura Molecular , Fenóis/química , Relação Estrutura-AtividadeRESUMO
A small series of C-glycosides containing the methoxyaryl moieties was tested for the inhibition of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from Cryptococcus neoformans and Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. The deprotected glycosides incorporating the 6-methoxy-2-naphthyl moiety showed the best inhibition profile and therefore represent leads for the development of novel anti-infectives with a new mechanism of action.
Assuntos
Brucella suis/enzimologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Cryptococcus neoformans/enzimologia , Glicosídeos/farmacologia , Naftalenos/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Naftalenos/químicaRESUMO
The transmembrane isoforms of carbonic anhydrase (hCA IX and XII) have been shown to be linked to carcinogenesis and their inhibition to arrest primary tumor and metastases growth. In this paper, we present a new class of C-glycosides incorporating the methoxyaryl moiety, that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. The glycosides have been prepared by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. We also present the inhibition profile of our new glycomimetics, against four isozymes of carbonic anhydrase comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (tumor associated isozymes). In this study, per-O-acetylated glycoside 4, 6 and deprotected compounds 7, 9, 10 and 12 were identified as potent and highly selective inhibitors of hCA IX and XII. These results confirm that attaching carbohydrate moieties to CA methoxyaryl pharmacophore improves and enhances its inhibitory activity. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.
Assuntos
Derivados de Benzeno/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Glicosídeos/farmacologia , Neoplasias/enzimologia , Derivados de Benzeno/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Glicosídeos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Neoplasias/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel ureido-sulfonamides was prepared by reaction of aminobenzenesulfonamide with alkyl/aryl isocyanate. These compounds are claimed for use as therapeutic agents of metastatic tumors, which are poorly responsive to classical chemotherapies and constitute a conceptually novel approach for cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Humanos , Metástase Neoplásica , Neoplasias/patologia , Patentes como Assunto , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/uso terapêuticoRESUMO
A small series of C-cinnamoyl glycoside containing the phenol moiety was tested for the inhibition of the three Mycobacterium tuberculosis ß-carbonic anhydrases (CAs, EC 4.2.1.1) with activities in the low micromolar range detected. The compounds were also tested for the inhibition of growth of M. tuberculosis H(37)Rv strain, leading to the identification of (E)-1-(2',3',4',6'-tetra-O-acetyl-ß-D-glucopyranosyl)-4-(3-hydroxyphenyl)but-3-en-2-one (1) as the first carbonic anhydrase inhibitor with anti-tubercular activity.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Glucosídeos/síntese química , Glucosídeos/farmacologia , Glicosídeos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Inibidores da Anidrase Carbônica/química , Cinamatos/química , Glucosídeos/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A small series of C-cinnamoyl glycosides incorporating the phenol moiety has been prepared by reaction of glycosyl ketones with the appropriate benzaldehydes. Glycosides were tested for the inhibition of twelve mammalian isoforms of carbonic anhydrase. This is the first study in which α-CAs have been investigated for their interaction with C-glycosides, a novel carbohydrate scaffold in the design of carbonic anhydrase inhibitors. The C-cinnamoyl glycosides were generally effective CA inhibitors, with inhibition constants in the low micromolar range against CA I, II, IV, VA, VB, VI, VII, IX, XII, XIII, XIV and ineffective inhibitors of CA III. These results confirm that attaching carbohydrate moieties to CA phenol pharmacophore improves its inhibitory activity.
Assuntos
Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Cinnamomum zeylanicum/química , Monossacarídeos/química , Animais , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/metabolismo , Glicosídeos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Cinética , Monossacarídeos/síntese química , Monossacarídeos/metabolismo , Ligação ProteicaRESUMO
The conformational behavior of 2,3,4,6-tetra-O-acetyl-ß-D-mannopyranosyl methanesulfonamide has been investigated from a combined theoretical and experimental point of view. The study of the conformational space of the glycosyl sulfonamide revealed that the ß anomer is thermodynamically more stable than the α one. This fact suggests that the synthesis reaction could take place mainly under thermodynamic control as the main experimental product is the ß-anomeric form of the sulfonamide. Several intramolecular hydrogen bonds were found in the stable conformers of the N-mannopyranosyl sulfonamide under study. A relationship was found to exist between them and the relative stability of the conformers. A detailed analysis of geometrical parameters shed light into the nature of the solid state structure of the novel 2,3,4,6-tetra-O-acetyl-ß-D-mannopyranosyl methanesulfonamide in terms of exo- and endo-anomeric effects and antiperiplanar relationships. NBO calculations confirmed those findings. Calculated (1)H and (13)C NMR chemical shifts support previous findings concerning configuration and conformation assignments of the title sulfonamide. Finally, an explanation of the stereochemical outcome of sulfonamidoglycosylations, was given in terms of exo- and endo-anomeric effects and steric factors.
Assuntos
Carboidratos/química , Manosídeos/química , Sulfonamidas/química , Acetilação , Configuração de Carboidratos , Carboidratos/síntese química , Glicosilação , Ligação de Hidrogênio , Manosídeos/síntese química , Modelos Moleculares , Sulfonamidas/síntese química , TermodinâmicaRESUMO
The transmembrane isoforms of carbonic anhydrase (CA IX and XII) have been shown to be linked to carcinogenesis and their inhibition to arrest primary tumor and metastases growth. In this Letter, we present a series of peracetylated and deprotected N-ß-glycosyl sulfamides that were tested for the inhibition of 4 carbonic anhydrase isoforms: the cytosolic hCA I and hCA II and transmembrane tumor-associated IX and XII. Compounds 1-4 and 6-8 selectively target cancer-associated CAs (IX and XII) with K(I)s in the low nanomolar range.
Assuntos
Amidas/química , Antígenos de Neoplasias/química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Amidas/síntese química , Amidas/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Neoplasias/enzimologia , Relação Estrutura-AtividadeRESUMO
The novel 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranosyl sulfamide, which exhibits selectivity for inhibiting isoform IX of carbonic anhydrase as overexpressed in many tumors, has been investigated from a combined theoretical and spectroscopic point of view. The conformational study of the compound shows that the α-anomeric form is more stable than the ß-anomeric form from a thermodynamic point of view after including solvent effects. This fact suggests that the synthesis reaction could take place mainly under thermodynamic control as the main experimental product is the α-anomeric form of the sulfamide. Calculated α/ß ratio is about 95:5, in excellent agreement with experimental data. Optimized geometries of the α-anomeric form agree quite well with crystallographic data. The inclusion of a solvent has negligible effects on the conformations. A detailed analysis of some geometric parameters shed light into the conformational behavior of the sulfamide in terms of both exo- and endo-anomeric effects and antiperiplanar relationships. Natural bond orbital calculations confirm those findings. Several intramolecular hydrogen bonds, characterized through the Atoms-in-Molecules theory, were found in the stable conformers. They, however, seem to play no relevant role in determining the relative stability of α conformers with respect to the ß ones. Calculated (1)H and (13)C NMR chemical shifts support previous findings concerning configuration and conformation assignments of the title sulfamide. The IR spectrum of the compound is recorded and reported for the first time and the assignment of some of the most important bands is accomplished with the aid of calculated harmonic vibrational frequencies.
Assuntos
Amino Açúcares/química , Antígenos de Neoplasias/química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Sulfonamidas/química , Anidrase Carbônica IX , Desenho de Fármacos , Humanos , Conformação Molecular , Simulação de Dinâmica Molecular , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A series of α-D-hex-2-enopyranosyl sulfonamides was evaluated for their antiproliferative activity against human hepatocellular liver carcinoma (HepG2) and human lung adenocarcinoma (A549) cell lines. The most potent compound (2,4,6-tri-O-acetyl-3-deoxy-α-D-erythro-hex-2-enopyranosyl ethanesulfonamide) showed antiproliferative properties in the micromolar range. The SARs of these sulfonamidoglycoside which includes the influence of carbohydrate rings and sulfonamide class are described.
Assuntos
Sulfonamidas/farmacologia , Adenocarcinoma/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Single crystal X-ray diffraction and high-resolution (1)H and (13)C NMR spectral data for 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hex-2-enopyranosyl sulfamide, a selective inhibitor of carbonic anhydrase isozyme IX, are reported. The (0)H(5) was found to be the preferred form for this glycosyl sulfamide, both in the crystal lattice and in solution.
Assuntos
Amino Açúcares/química , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Cristalografia por Raios X/métodos , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Conformação MolecularRESUMO
A series of novel N-glycosyl sulfonamides were prepared via Ferrier sulfonamidoglycosylation of D-glycals with good to high alpha-stereoselectivity. Two new glycosylsulfamides were tested as carbonic anhydrase (CA II) inhibitors and showed good properties in the micromolar range.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Glicosídeos/química , Glicosilação , Sulfonamidas/química , Configuração de Carboidratos , Catálise , Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Químicos , Conformação Molecular , EstereoisomerismoRESUMO
A series of glycosylated sulfamides possessing a diverse substitution pattern, with benzylated, peracetylated, and unsaturated six- and five-membered ring sugar moieties attached to the NHSO(2)NH(2) zinc binding group is reported. These derivatives were tested for the inhibition of five human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IV, IX, and XII. Against hCA I the sulfamides behaved as weak inhibitors, whereas they showed low nanomolar activity against hCA II, IX, and XII, being slightly less effective as hCA IV inhibitors. One compound showed selectivity for inhibiting the tumor-associated isoforms hCA IX and XII over the ubiquitous cytosolic hCA II. The sulfamide zinc binding group may thus indeed lead to very effective glycosylated inhibitors targeting several physiologically relevant isozymes.
Assuntos
Amidas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Isoenzimas/antagonistas & inibidores , Amidas/química , Inibidores da Anidrase Carbônica/química , Isoenzimas/químicaRESUMO
[reaction: see text] The sulfonamidoglycosylation of benzylated glycals using a catalytic amount of triphenylphosphine hydrobromide proceeded in a highly stereoselective fashion to give the beta anomers with good to high yields. This process was demonstrated with d-galactal and d-glucal. Two of the new N-2-(deoxyglycosyl)sulfonamides were tested as inhibitors of tumor cell growth in vitro and showed antiproliferative properties in the micromolar range.