RESUMO
A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 µM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 µM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sulfanilamidas/síntese química , Sulfanilamidas/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Sulfanilamidas/administração & dosagem , Triazóis/administração & dosagem , Triazóis/síntese química , Triazóis/farmacologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/administração & dosagemRESUMO
Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene-sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N-Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (≥95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures.
Assuntos
Aminoácidos/química , Benzeno/química , Sulfanilamidas/química , Triazinas/química , Técnicas de Química Sintética , Humanos , Estrutura Molecular , Sulfanilamida , Sulfanilamidas/síntese químicaRESUMO
The cantharidinimide derivatives, 5a-h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i-k, 11l-n, 12o-p, and 16q-s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.
Assuntos
Anidridos/farmacologia , Antineoplásicos/síntese química , Aziridinas/química , Cantaridina/síntese química , Sulfanilamidas/farmacologia , Anidridos/síntese química , Antineoplásicos/farmacologia , Cantaridina/análogos & derivados , Cantaridina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Oxazóis/química , Pirazóis/química , Pirimidinas/química , Relação Estrutura-Atividade , Sulfanilamidas/síntese química , Tiazóis/químicaRESUMO
Reaction of γ-Boc-GABA, prepared by protecting the γ-amino moiety of the amino butyric acid with the tert-butyloxycarbonyl (Boc) protecting group, with 4-methyl/ethyl benzenesulfonamide, followed by removal of the Boc protecting group in 3 M HCl afforded the corresponding hydrochlorides, which were further derivatized by reaction with a varying of aryl isocyanates to give a new classes of ureido substituted benzenesulfonamide containing a GABA moiety. Inhibition studies of the human carbonic anhydrase(CA, EC 4.2.1.1) isoforms, CA IXIV with these new compounds revealed that they possess moderate-weak inhibition potency against hCA III, IV, VA, VI and XIII, rather efficient inhibitory power against hCA I, VI, and IX, and excellent inhibition of the physiologically relevant hCA II and VII, as well as of the two tumor-associated isoforms CA IX and XII. The inhibition profile of the new ureido-substituted benzenesulfonamides reported here is thus very different from the corresponding ureido-substituted analogs incorporating sulfanilamide, which were previously investigated as inhibitors of some of these enzymes.
Assuntos
Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Sulfanilamidas/química , Ácido gama-Aminobutírico/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/química , Anidrases Carbônicas/genética , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Ligação Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/síntese química , Sulfanilamidas/metabolismoRESUMO
A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 µM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.
Assuntos
Antineoplásicos/síntese química , Benzodiazepinas/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sulfanilamidas/síntese química , Triazóis/síntese química , Proteína Supressora de Tumor p53/metabolismo , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Sulfanilamidas/química , Sulfanilamidas/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
A series of sulfonamides incorporating the sulfanilamide (SA) scaffold were prepared. Reaction of the 4-amino moiety of SA with benzyl chlorides or substituted bromoacetophenones afforded the 4-mono-alkylated derivatives which were then reacted with 1,1,1-trifluoro-4-isobutoxybut-3-en-2-one leading to a series of 4-N,N-disubstituted SAs. The key intermediates were also reacted with ethoxycarbonyl isothiocyanate leading to thioureas or were cyclized in the presence of potassium cyanate/isothiocyanate to the corresponding imidazol-2(3H)-one/thiones. The new compounds were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, and the transmembrane, tumor-associated CA IX and XII. These sulfonamides were ineffective CA I and II inhibitors but were nanomolar CA IX and XII inhibitors, making them of interest as clinical candidates for antitumor/antimetastasis applications.
Assuntos
Butanonas/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Imidazóis/química , Sulfanilamidas/farmacologia , Tionas/química , Tioureia/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfanilamidas/síntese química , Sulfanilamidas/químicaRESUMO
The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.
Assuntos
Piperidinas/química , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfanilamidas/síntese química , Sulfanilamidas/farmacologia , Proteínas Wnt/metabolismo , Animais , Linhagem Celular Tumoral , Genes Reporter/genética , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Isomerismo , Camundongos , Estrutura Molecular , Ligação Proteica , Crânio/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfanilamidas/química , Proteínas Wnt/genéticaRESUMO
A series of sulfonamides has been obtained by reacting sulfanilamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide with omega-chloroalkanoyl chlorides, followed by replacement of the omega-chlorine atom with secondary amines. Tails incorporating heterocyclic amines belonging to the morpholine, piperidine and piperazine ring systems have been attached to these sulfonamides, by means of an alkanoyl-carboxamido linker containing from two to five carbon atoms. The new derivatives prepared in this way were tested as inhibitors of three carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic isozymes CA I and II, and the catalytic domain of the transmembrane, tumor-associated isozyme CA IX. Several low nanomolar CA I and CA II inhibitors were detected both in the aromatic and heterocyclic sulfonamide series, whereas the best hCA IX inhibitors (inhibition constants in the range of 22-35 nM) all belonged to the acetazolamide-like derivatives.
Assuntos
Acetazolamida/síntese química , Inibidores da Anidrase Carbônica/síntese química , Isoenzimas/metabolismo , Sulfanilamidas/síntese química , Acetazolamida/farmacologia , Aminas/química , Biomarcadores Tumorais , Inibidores da Anidrase Carbônica/farmacologia , Catálise , Citosol/enzimologia , Compostos Heterocíclicos/química , Humanos , Isoenzimas/classificação , Morfolinas/química , Piperazina , Piperazinas/química , Piperidinas/química , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/farmacologiaRESUMO
Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.
Assuntos
Antineoplásicos/síntese química , Derivados de Benzeno/síntese química , Inibidores Enzimáticos/síntese química , Proteínas de Neoplasias/antagonistas & inibidores , Sulfonamidas/síntese química , Antígenos de Neoplasias/química , Antineoplásicos/química , Derivados de Benzeno/química , Bromo/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica IV/antagonistas & inibidores , Anidrase Carbônica IV/química , Anidrase Carbônica IX , Anidrases Carbônicas/química , Cloro/química , Inibidores Enzimáticos/química , Humanos , Iodo/química , Proteínas de Neoplasias/química , Relação Estrutura-Atividade , Sulfanilamidas/síntese química , Sulfanilamidas/química , Sulfonamidas/químicaRESUMO
RO-04-6790 (6a) has been identified in a random screen for 5-HT(6) receptor antagonists. In a medicinal chemistry optimisation program a series of analogs comprising N-heteroaryl- and N-arylbenzenesulfonamides have been synthesised and investigated for their binding affinity. Compounds with a logD profile indicative of brain penetration have been subjected to in vivo testing for reversal of a scopolamine-induced retention deficit in a passive avoidance paradigm.
Assuntos
Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Ligação Competitiva , Disponibilidade Biológica , Humanos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Ligação Proteica , Pirimidinas , Ratos , Escopolamina , Antagonistas da Serotonina/farmacocinética , Sulfanilamida , Sulfanilamidas/síntese química , Sulfanilamidas/farmacocinética , Sulfanilamidas/farmacologiaRESUMO
benzoxazolone-5-(2'-nitro)-sulphonanilides were synthesized by acylation of o-nitroanilines with benzoxazolone-5-sulphochloride or 3-methylbenzoxazolone-5-sulphochloride. The nitro group in these compounds was subjected to reduction and the resulting amino derivatives were cyclysed to yield the corresponding 1-(benzoxazolone-5'-sulphonyl)-benzotriazoles. Decyclization of the oxazolone cycle of benzoxazolone-5-(2'-amino)-sulphonanilides resulted in 4-hydroxy-3,2'-diaminobenzenesulphonanilides. In vitro testing of the antiviral activity of the compounds obtained during successive synthetic steps revealed that some of them exhibited marked antiviral effect against toga, orthomixo, oncorna and herpes viruses.
Assuntos
Antivirais/síntese química , Benzoxazóis/síntese química , Sulfanilamidas/síntese química , Animais , Antivirais/farmacologia , Benzoxazóis/farmacologia , Fenômenos Químicos , Química , Efeito Citopatogênico Viral/efeitos dos fármacos , Herpesvirus Suídeo 1/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Leucemia Murina de Moloney/efeitos dos fármacos , Vírus da Floresta de Semliki/efeitos dos fármacos , Sulfanilamidas/farmacologia , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
Twenty-two 1-p-sulfamoylphenyl-3,3-dialkyltriazenes, 1-p-dialkylsulfamoylphenyl-3,3-dialkyltriazenes, and 1-p-[N,N-bis(2-chloroethyl) sulfamoylphenyl] -3,3-dialkyltriazenes were synthesized from their corresponding amines. Six of the compounds tested were devoid of antitumor activity.
Assuntos
Antineoplásicos , Compostos de Mostarda Nitrogenada , Triazenos , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Leucemia L1210/tratamento farmacológico , Camundongos , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/uso terapêutico , Sulfanilamidas/síntese química , Sulfanilamidas/uso terapêutico , Triazenos/síntese química , Triazenos/uso terapêuticoRESUMO
The preparation of quaternary ammonium derivatives of sulfanilamide and of tertiary amines containing an aliphatic chain up to c-18 is described. Some members of this series show greater antimicrobial activity than the parent substances. This is found also in comparison with other analogous series which have been prepared.