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1.
Nat Commun ; 11(1): 3859, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737298

RESUMO

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins.


Assuntos
Anidrase Carbônica II/química , Preparações de Ação Retardada/síntese química , Hidrogéis/química , Ribonucleases/química , Sefarose/química , Animais , Anticorpos/química , Avidina/química , Biotina/química , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Bovinos , Ativação Enzimática , Transição de Fase , Reologia , Ribonucleases/antagonistas & inibidores , Sulfonamidas/química
2.
J Med Chem ; 63(13): 7422-7444, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32519851

RESUMO

The "tail approach" has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at the middle/outer active sites rim, which could be targeted to increase the CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs (TTI) to fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure-activity relationship (SAR) study was carried out with 32 such benzenesulfonamides differing in tails combination that were assayed for hCAs I, II, IV, and XII inhibition. A structural study was undertaken by X-ray crystallography and in silico tools to assess the ligand/target interaction mode. The most active and selective inhibitors against isoforms implicated in glaucoma were assessed in a rabbit model of the disease achieving an intraocular pressure-lowering action comparable to the clinically used dorzolamide.


Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/química , Animais , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Simulação por Computador , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular/efeitos dos fármacos , Ligantes , Masculino , Estudo de Prova de Conceito , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia
3.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
4.
J Med Chem ; 63(13): 7392-7409, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32463228

RESUMO

Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with KI values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC50 values ranging from 5.2 to 9.1 µM). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Telomerase/antagonistas & inibidores , Zidovudina/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Reação de Cicloadição , Desenho de Fármacos , Células HT29 , Humanos , Células PC-3 , Relação Estrutura-Atividade , Telomerase/genética , Telomerase/metabolismo , Triazóis/química
5.
Eur J Med Chem ; 200: 112300, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32460112

RESUMO

Oxathiino[6,5-b]pyridine 2,2-dioxides are identified as a new class of isoform-selective nanomolar inhibitors of tumor associated human carbonic anhydrases (hCA) IX and XII. At the same time they do not inhibit or poorly inhibit cytosolic isoforms hCA I and II. Oxathiino[6,5-b]pyridine 2,2-dioxides exhibited good antiproliferative properties on tumor cell lines MCF-7 (Human breast adenocarcinoma), A549 (human lung (alveolar) adenocarcinoma) and HeLa (epithelioid cervix carcinoma).


Assuntos
Antineoplásicos/química , Inibidores da Anidrase Carbônica/farmacologia , Neoplasias/enzimologia , Piridinas/farmacologia , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Piridinas/química
6.
J Med Chem ; 63(8): 4306-4314, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223141

RESUMO

We report for the first time a novel series of tellurides bearing sulfonamide as selective and potent inhibitors of the ß-class carbonic anhydrase (CA; EC 4.2.1.1) enzyme expressed in Leishmania donovani protozoa. Such derivatives showed high activity against axenic amastigotes, and among them, compound 5g (4-(((3,4,5-trimethoxyphenyl)tellanyl)methyl)benzenesulfonamide) showed an IC50 of 0.02 µM being highly selective for the parasites over THP-1 cells with a selectivity index of 300. The in vitro and in vivo toxicity experiments showed compound 5g to possess a safe profile and thus paving the way for tellurium-containing compounds as novel drug entities.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Leishmania donovani/efeitos dos fármacos , Sulfonamidas/farmacologia , Tripanossomicidas/farmacologia , Animais , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Feminino , Jejuno/efeitos dos fármacos , Jejuno/patologia , Leishmania donovani/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Sulfonamidas/química , Tripanossomicidas/química
7.
J Enzyme Inhib Med Chem ; 35(1): 733-743, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32189526

RESUMO

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2-20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12-17, and 19-20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27-195 and 3.2-19, respectively, while compounds 12, 14-17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48-158 and 5.4-31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.HighlightsQuinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised.The new molecules potently inhibited the hCA isoforms I, II, IV, and IX.Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 12-17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 12, 14-17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12-17, and 19-20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14-17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/química , Relação Estrutura-Atividade , Sulfonamidas/química
8.
Eur J Med Chem ; 193: 112219, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203788

RESUMO

Two new series of 1,3,4-oxadiazole benzenesulfonamide hybrids 3 and 4, having twenty novel compounds, have been designed and synthesized in order to assess their inhibition potential as CAIs against hCA I, II, IX, and XII. 'Tail approach' strategy has been used to design the aromatic sulfonamide scaffolds with carbonyl and amide linker. Excellent inhibitory activity against hCA I has been exhibited by compounds 3g and 4j, 3.5 magnitude of order better than reference drug AAZ (KI = 250 nM). Moreover, compound 4j (KI = 7.9 nM) effectively inhibited glaucoma-associated hCA II isoform as well as tumor-associated hCA IX isoform with KI = 16.3 nM. Further hCA XII was weakly inhibited by all the compounds with KI values ranging from 0.23 µM to 3.62 µM. Interestingly structure-activity relationship (SAR) study indicates that N-(3-nitrophenyl)-2-((5-(4-sulfamoylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide (4j) is a potent compound to be investigated further for antiglaucoma and antitumor activity. The chemistry of the nature of different substitutions on the 1,3,4-oxadiazole bearing benzenesulfonamide substituted aromatic ring for potency and selectivity over one hCA isoform versus others is deliberated in the present study. In this context, the 1,3,4-oxadiazole motif can be a valuable tool worth developing for the procurement of novel and potent selective CAIs potentially useful for the management of a variety of diseases as chemotherapeutic agents.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Oxidiazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
9.
J Enzyme Inhib Med Chem ; 35(1): 598-609, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32009479

RESUMO

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2-13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2-13 with inhibition constants (KIs) ranging from 57.8-740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2-13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
10.
Org Lett ; 22(4): 1396-1401, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32013455

RESUMO

Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.


Assuntos
Acrilatos/química , Inibidores da Anidrase Carbônica/síntese química , Ácidos Carboxílicos/síntese química , Cobre/química , Compostos de Diazônio/química , Triazóis/síntese química , Inibidores da Anidrase Carbônica/química , Ácidos Carboxílicos/química , Estrutura Molecular , Sais/química , Triazóis/química
11.
J Enzyme Inhib Med Chem ; 35(1): 622-628, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037900

RESUMO

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (KIs of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazinas/farmacologia , Compostos Organometálicos/farmacologia , Sulfonamidas/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/química
12.
Molecules ; 25(5)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32106611

RESUMO

A new ß-class carbonic anhydrase was cloned and purified from the filamentous ascomycete Sordaria macrospora, CAS3. This enzyme has a higher catalytic activity compared to the other two such enzymes from this fungus, CAS1 and CAS2, which were reported earlier, with the following kinetic parameters: kcat of (7.9 ± 0.2) × 105 s-1, and kcat/Km of (9.5 ± 0.12) × 107 M-1∙s-1. An inhibition study with a panel of sulfonamides and one sulfamate was also performed. The most effective CAS3 inhibitors were benzolamide, brinzolamide, dichlorophnamide, methazolamide, acetazolamide, ethoxzolamide, sulfanilamide, methanilamide, and benzene-1,3-disulfonamide, with KIs in the range of 54-95 nM. CAS3 generally shows a higher affinity for this class of inhibitors compared to CAS1 and CAS2. As S. macrospora is a model organism for the study of fruiting body development in fungi, these data may be useful for developing antifungal compounds based on CA inhibition.


Assuntos
Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Sordariales/enzimologia , Relação Estrutura-Atividade , Acetazolamida/química , Sequência de Aminoácidos/genética , Benzolamida/química , Inibidores da Anidrase Carbônica/classificação , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/genética , Anidrases Carbônicas/isolamento & purificação , Etoxzolamida/química , Humanos , Cinética , Metazolamida/química , Sulfanilamida/química , Sulfonamidas/química , Tiazinas/química
13.
J Enzyme Inhib Med Chem ; 35(1): 650-656, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32079427

RESUMO

A series of 3H-1,2-benzoxathiepine 2,2-dioxides incorporating 7-acylamino moieties were obtained by an original procedure starting from 5-nitrosalicylaldehyde, which was treated with propenylsulfonyl chloride followed by Wittig reaction of the bis-olefin intermediate. The new derivatives, belonging to the homosulfocoumarin chemotype, were assayed as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Four pharmacologically relevant human (h) isoforms were investigated, the cytosolic hCA I and II and the transmembrane, tumour-associated hCA IX and XII. No relevant inhibition of hCA I and II was observed, whereas some of the new derivatives were effective, low nanomolar hCA IX/XII inhibitors, making them of interest for investigations in situations in which the activity of these isoforms is overexpressed, such as hypoxic tumours, arthritis or cerebral ischaemia.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Tiepinas/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Tiepinas/síntese química , Tiepinas/química
14.
J Enzyme Inhib Med Chem ; 35(1): 539-548, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31948300

RESUMO

In an in vitro screening for human carbonic anhydrase (hCA) inhibiting agents from higher plants, the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds selectively inhibited hCA IX and hCA XII isoforms. The phytochemical investigation of the extracts led to the isolation of ten linear furocoumarins (1-10), four simple coumarins (12-15) and a new angular dihydrofurocoumarin (11). The structures of the isolated compounds were elucidated based on 1 D and 2 D NMR, MS, and ECD data analysis. All isolated compounds were inactive towards the ubiquitous cytosolic isoform hCA I and II (Ki > 10,000 nM) while they were significantly active against the tumour-associated isoforms hCA IX and XII. Umbelliprenin was the most potent coumarin inhibiting hCA XII isoform with a Ki of 5.7 nM. The cytotoxicity of the most interesting compounds on HeLa cancer cells was also investigated.


Assuntos
Apiaceae/química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/isolamento & purificação , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Simulação por Computador , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Sementes/química , Relação Estrutura-Atividade
15.
Arch Pharm (Weinheim) ; 353(3): e1900292, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922298

RESUMO

The inhibition of the two human cytosolic carbonic anhydrase (hCA; EC 4.2.1.1) isozymes I and II with some new pyrazoline derivatives was investigated for the first time. The structures of the newly synthesized pyrazoline derivatives were characterized by Fourier transform-infrared spectroscopy, 1 H-/13 C-nuclear magnetic resonance, and mass spectrometry, and elemental analysis. Compounds 1-6 showed Ki values in the range of 16.4-205.9 nM for hCA I and of 6.08-93.21 nM against hCA II. These hydroxyl and amino group-containing compounds generally were competitive inhibitors. The compounds investigated here showed effective hCA I and II inhibitory effects, in the same range as the clinically used acetazolamide, and might be used as leads for generating enzyme inhibitors, possibly targeting other CA isoforms that have not yet been assayed for their interactions with such agents.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Pirazóis/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
16.
J Med Chem ; 63(5): 2470-2488, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31972093

RESUMO

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.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sacarina/química , Sacarina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Linhagem Celular , Reação de Cicloadição , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Sacarina/síntese química
17.
J Enzyme Inhib Med Chem ; 35(1): 549-554, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31967484

RESUMO

A small series of 2,4-dioxothiazolidinyl acetic acids was prepared from thiourea, chloroacetic acid, aromatic aldehydes, and ethyl-2-bromoacetate. They were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, the cytosolic hCA I and II, and the transmembrane hCA IX and XII, involved among others in tumorigenesis (hCA IX and XII) and glaucoma (hCA II and XII). The two cytosolic isoforms were not inhibited by these carboxylates, which were also rather ineffective as hCA IX inhibitors. On the other hand, they showed submicromolar hCA XII inhibition, with KIs in the range of 0.30-0.93 µM, making them highly CA XII-selective inhibitors.


Assuntos
Acetatos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/classificação , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Tiazóis/farmacologia , Acetatos/síntese química , Acetatos/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
18.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963423

RESUMO

A series of 2-thio- and 2-seleno-acetamides bearing the benzenesulfonamide moiety were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against different pathogenic bacteria such as the Vibrio cholerae (VchCA-α and VchCA-ß), Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ), Mycobacterium tuberculosis (Rv3723-ß) and the Salmonella enterica serovar Typhimurium (StCA2-ß). The molecules represent interesting leads worth developing as innovative antibacterial agents since they possess new mechanism of action and isoform selectivity preferentially against the bacterial expressed CAs. The identification of potent and selective inhibitors of bacterial CAs may lead to tools also useful for deciphering the physiological role(s) of such proteins.


Assuntos
Acetamidas/química , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Infecções Bacterianas/tratamento farmacológico , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Sulfonamidas/química , Bactérias/enzimologia , Infecções Bacterianas/microbiologia , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organosselênicos/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Sulfonamidas/farmacologia
19.
Eur J Med Chem ; 189: 112019, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972394

RESUMO

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with KIs ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC50 = 6.4, 8.0 and 11.6 µM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.


Assuntos
Antineoplásicos/farmacologia , Compostos Azo/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Pirazóis/química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/química , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/patologia , Relação Estrutura-Atividade , Sulfonamidas/química
20.
J Enzyme Inhib Med Chem ; 35(1): 489-497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914827

RESUMO

A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.


Assuntos
Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
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