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1.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
2.
Acta Crystallogr D Struct Biol ; 75(Pt 10): 895-903, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588921

RESUMO

Human carbonic anhydrase IX (CA IX) expression is upregulated in hypoxic solid tumours, promoting cell survival and metastasis. This observation has made CA IX a target for the development of CA isoform-selective inhibitors. To enable structural studies of CA IX-inhibitor complexes using X-ray and neutron crystallography, a CA IX surface variant (CA IXSV; the catalytic domain with six surface amino-acid substitutions) has been developed that can be routinely crystallized. Here, the preparation of protiated (H/H), H/D-exchanged (H/D) and deuterated (D/D) CA IXSV for crystallographic studies and their structural comparison are described. Four CA IXSV X-ray crystal structures are compared: two H/H crystal forms, an H/D crystal form and a D/D crystal form. The overall active-site organization in each version is essentially the same, with only minor positional changes in active-site solvent, which may be owing to deuteration and/or resolution differences. Analysis of the crystal contacts and packing reveals different arrangements of CA IXSV compared with previous reports. To our knowledge, this is the first report comparing three different deuterium-labelled crystal structures of the same protein, marking an important step in validating the active-site structure of CA IXSV for neutron protein crystallography.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Domínio Catalítico , Modelos Moleculares , Clonagem Molecular , Cristalografia por Raios X/métodos , Deutério , Escherichia coli/genética , Humanos
3.
Molecules ; 24(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590289

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Cumarínicos/síntese química , Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Domínio Catalítico , Simulação por Computador , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 181: 111586, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401537

RESUMO

We have synthetized a novel series of ß-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a ß-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48 h incubation in normoxic conditions killing over 50% of tumor cells at 3 µM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30 µM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Telúrio/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Feminino , Humanos , Simulação de Acoplamento Molecular , Sulfonamidas/síntese química , Sulfonamidas/química , Telúrio/química
5.
Molecules ; 24(13)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262068

RESUMO

To find novel human carbonic anhydrase (hCA) inhibitors, we synthesized thirteen compounds by combining thiazolidinone with benzenesulfonamide. The result of the X-ray single-crystal diffraction experiment confirmed the configuration of this class of compounds. The enzyme inhibition assays against hCA II and IX showed desirable potency profiles, as effective as the positive controls. The docking studies revealed that compounds (2) and (7) efficiently bound in the active site cavity of hCA IX by forming sufficient interactions with active site residues. The fragment of thiazolidinone played an important role in the binding of the molecules to the active site.


Assuntos
Antígenos de Neoplasias , Anidrase Carbônica II , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica , Simulação de Acoplamento Molecular , Sulfonamidas , Antígenos de Neoplasias/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico , Humanos , Sulfonamidas/síntese química , Sulfonamidas/química
6.
Chem Commun (Camb) ; 55(40): 5720-5723, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31038135

RESUMO

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigated in vitro as a human (h) Carbonic Anhydrase Inhibitor (CAI). The kinetic data clearly show, for the first time, EPA to be a highly effective and selective inhibitor for the tumor-associated isoforms hCA IX/XII. We report the high resolution X-ray crystal structure of the EPA-hCA II adduct, and assessed its binding mode to CA IX/XII by means of computational techniques. EPA may exert antitumor effects also due to the potent inhibition of the tumor-associated CAs.


Assuntos
Anidrase Carbônica IX/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Neoplasias/enzimologia , Oximas/farmacologia , Polifarmacologia , Sulfonamidas/farmacologia , Anidrase Carbônica IX/química , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/química , Sulfonamidas/química
7.
Int J Mol Sci ; 20(9)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083645

RESUMO

Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed KI values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites.


Assuntos
Antineoplásicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Humanos , Hidrazonas/química , Indóis/química , Simulação de Acoplamento Molecular , Ligação Proteica , Sulfonamidas/química
8.
Comput Biol Chem ; 80: 307-313, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078112

RESUMO

In this study, we present four multilinear regression quantitative structure-activity relationship (QSAR) models, the first of which tackles the experimental CA IX isozyme inhibitory activities of a mixed set of 59 compounds (coumarins and sulfocoumarins), while the second and the third ones are local models for coumarins (42 compounds) and sulfocoumarins (17 compounds) for the same endpoint respectively. The fourth model deals with the selective inhibitory activity of 29 compounds on CA II and CA IX isozymes which was defined as differences of inhibition constants between CA II and CA IX (ΔpKi=pKi_CAII- pKi_CAIX) in logarithmic scale. All presented models are statistically significant, robust and internally and externally validated. Most of the descriptors involved in these models are DFT-based physically-interpretable ones. Existence of the eigenvalues of chemical reactivity-related orbitals such as HOMO-1 Energy and LUMO Energy in the models allow us to speculate that the hydrolyzing reactions of the coumarins and sulfocoumarins in the active pocket of CA isozymes play a critical role in (or modulate) the binding free energy of the ligand-isozyme complexes. We believe that presented models may be used to design new virtual analogues of existing compounds with desired activity and selectivity towards CA IX or CA II.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Cumarínicos/química , Relação Quantitativa Estrutura-Atividade , Teoria da Densidade Funcional , Humanos , Modelos Químicos , Estrutura Molecular
9.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137489

RESUMO

In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a-h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (KIs: 8.3-123.3 and 9.8-134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (KIs = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a-g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC50 = 4.89 ± 0.22 µM) than the reference drug Staurosporine (IC50 = 7.25 ± 0.43 µM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.


Assuntos
Antineoplásicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/química , Antineoplásicos/farmacologia , Derivados de Benzeno/química , Sítios de Ligação , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica
10.
Comput Biol Chem ; 80: 234-243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009872

RESUMO

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R2>0.75) and predictability (Q2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica II/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Conjuntos de Dados como Assunto , Desenho de Drogas , Humanos , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
11.
Int J Mol Sci ; 20(5)2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30857344

RESUMO

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.


Assuntos
Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Cumarínicos/química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Cumarínicos/farmacologia , Humanos , Simulação de Acoplamento Molecular
12.
Eur J Med Chem ; 162: 147-160, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445264

RESUMO

Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7-86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192-239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 ±â€¯0.28 and 12.90 ±â€¯0.34 µM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.


Assuntos
Antineoplásicos/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Isatina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/farmacologia , Domínio Catalítico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Isatina/química , Simulação de Acoplamento Molecular , Compostos de Fenilureia/farmacologia , Ligação Proteica , Sulfonamidas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
13.
Bioorg Chem ; 83: 549-558, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471577

RESUMO

SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21-7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (KI = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - >35714), hCA II (SI: 2 - 1689) and hCA IV (SI: 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.


Assuntos
Compostos de Anilina/farmacologia , Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Ensaios Enzimáticos , Humanos , Cinética , Estrutura Molecular , Compostos de Fenilureia/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Molecules ; 24(1)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577607

RESUMO

We herein describe a flexible synthesis of a small library of 68Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1⁻3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives (8 and 9) yielded six new 68Ga-labeled CAIX ligands with high radiochemical yields. The click reaction conditions were optimized to improve the reaction rate for applications with short half-life radionuclides. Overall, our methodology allows for a simple and efficient radiosynthetic route to produce a variety of 68Ga-labeled imaging agents for tumor hypoxia.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Anidrase Carbônica IX/química , Química Click , Radioisótopos de Gálio/química , Nitrilos/química , Nitrilos/farmacologia , Benzotiazóis/síntese química , Cromatografia Líquida de Alta Pressão , Humanos , Marcação por Isótopo , Nitrilos/síntese química , Compostos Radiofarmacêuticos , Bibliotecas de Moléculas Pequenas
16.
J Med Chem ; 61(23): 10860-10874, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30433782

RESUMO

Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia-activated antitumor CAIs.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Anidrase Carbônica IX/química , Anidrases Carbônicas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Humanos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade
17.
Bioorg Chem ; 81: 642-648, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30253337

RESUMO

Several new molecules with different thio-scaffolds were designed, synthesised, and evaluated biologically as inhibitors of Carbonic Anhydrases (CAIs). The structure-activity relationship analysis identified thioether derivatives, here reported, as a potent and selective CAIs against hCA II and hCA IX. High resolution X-ray structure of inhibitor bound hCA II revealed extensive interactions with the hydrophobic pocket of active site and provided molecular insight into the binding properties of these new inhibitors.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Sulfonamidas/síntese química
18.
J Enzyme Inhib Med Chem ; 33(1): 1299-1308, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30249139

RESUMO

A small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 µM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Tiazolidinas/química , Tiazolidinas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Relação Dose-Resposta a Droga , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/química , Sulfanilamidas/farmacologia , Tiazolidinas/síntese química , Zinco/química , Zinco/farmacologia
19.
J Enzyme Inhib Med Chem ; 33(1): 1430-1443, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30220229

RESUMO

In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logkw) and inhibitory activity (logKi) were used as drug properties. Genetic algorithm-partial least squares (GA-PLS) provided a QSPR model with high prediction capability employing only seven molecular descriptors. As a proof-of-concept, optimal drug structure was obtained by inverting the model with respect to reference drug properties. 3509 ligands were ranked accordingly. Top 10 ligands were further validated through molecular docking. Large-scale MD simulations were performed to test the stability of structures of selected ligands obtained through docking complemented with biophysical experiments.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Sulfanilamidas/química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/síntese química , Cromatografia Líquida , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Sulfanilamida
20.
Eur J Med Chem ; 156: 61-78, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006175

RESUMO

Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.


Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Drogas , Sulfonamidas/química , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Sítios de Ligação , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Halogenação , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Termodinâmica
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