RESUMO
Protein-protein interactions (PPI) represent attractive targets for drug design. Thus, aiming at a deeper insight into the HSV-1 envelope glycoprotein D (gD), protein-protein docking and dynamic simulations of gD-HVEM and gD-Nectin-1 complexes were performed. The most stable complexes and the pivotal key residues useful for gD to anchor human receptors were identified and used as starting points for a structure-based virtual screening on a library of both synthetic and designed 1,2,3-triazole-based compounds. Their binding properties versus gD interface with HVEM and Nectin-1 along with their structure-activity relationships (SARs) were evaluated. Four [1,2,3]triazolo[4,5-b]pyridines were identified as potential HSV-1 gD inhibitors, for their good theoretical affinity towards all conformations of HSV-1 gD. Overall, this study suggests promising basis for the design of new antiviral agents targeting gD as a valuable strategy to prevent viral attachment and penetration into the host cell.
Assuntos
Herpesvirus Humano 1 , Humanos , Nectinas/metabolismo , Herpesvirus Humano 1/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptores Virais/metabolismo , Proteínas do Envelope Viral/químicaRESUMO
A series of [1,2]oxazolo[5,4-e]isoindole derivatives was evaluated against HL-60 cell line and its multidrug resistance (MDR) variant, HL-60R, resistant to doxorubicin and to other P-gp substrates by overexpressing the efflux pump. They displayed antiproliferative activities, with IC50 values ranging from 0.02 to 5.5 µM. In particular, the newly synthesized compound 4k produced synergistic effects in terms of cell growth inhibition and cell death induction either in combination with a Vinca alkaloid, Vinblastine, and a Taxane, Paclitaxel in HL-60R cells. The study of the mechanism of action indicated that all compounds showed antimitotic activity through inhibition of tubulin polymerization. Thus, [1,2]oxazoles could represent a valuable tool to overcome MDR mechanism, confirming the potential use of this class of compounds.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Isoindóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.
Assuntos
Antineoplásicos , Mieloma Múltiplo , Alcaloides de Vinca , Humanos , Trifosfato de Adenosina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Calreticulina/metabolismo , Linhagem Celular Tumoral , Colchicina/farmacologia , Morte Celular Imunogênica , Isoindóis/farmacologia , Microtúbulos/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Oxazóis/farmacologia , Taxoides/farmacologia , Alcaloides de Vinca/farmacologia , Pemetrexede/farmacologia , Pemetrexede/uso terapêuticoRESUMO
Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.
Assuntos
Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Proteínas Mutantes/genética , Aminoimidazol Carboxamida/química , Benzodioxóis/química , Fibrose Cística/genética , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Mutação/efeitos dos fármacos , Mutação/genética , Dobramento de Proteína/efeitos dos fármacos , Tiazóis/químicaRESUMO
The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.
Assuntos
Antineoplásicos/química , Organismos Aquáticos/química , Toxinas Marinhas/química , Animais , Produtos Biológicos , Descoberta de Drogas , Humanos , Neoplasias/tratamento farmacológico , Microbiologia da ÁguaRESUMO
BACKGROUND: The stems of Opuntia ficus-indica, known as cladodes, are a rich source of soluble fibers, which makes them an important candidate for the production of functional foods. Tagliatelle of durum wheat fortified with Opuntia cladode extract (OCE) at different levels of addition (10-30%, v/w) was prepared on a laboratory scale and quality characteristics and sensory acceptability were assessed. RESULTS: The main quality parameters (optimal cooking time, swelling index, cooking loss, dry matter) and sensory analysis on a nine-point hedonic scale were comparable with those of the control pasta sample (no added OCE) when durum wheat was supplemented with OCE at up to 20% (v/w). An in vitro human simulated gastrointestinal digestion in the presence of cholesterol or its main dietary oxidized derivative, 7-ketocholesterol, showed that OCE-fortified pasta strongly reduced the bioaccessibility of both the sterols (the higher the incorporated OCE level, the higher the effect). Moreover the extent of starch digestion decreased with increasing levels of OCE. CONCLUSION: The results of the present study indicate that OCE-fortified pasta comprises a food with healthy properties, such as blood cholesterol- and glucose-lowering capabilities. © 2019 Society of Chemical Industry.
Assuntos
Alimentos Fortificados/análise , Alimento Funcional/análise , Opuntia/química , Extratos Vegetais/análise , Extratos Vegetais/metabolismo , Triticum/química , Adulto , Idoso , Culinária , Fibras na Dieta/análise , Fibras na Dieta/metabolismo , Digestão , Feminino , Trato Gastrointestinal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Opuntia/metabolismo , Controle de Qualidade , Paladar , Triticum/metabolismo , Adulto JovemRESUMO
New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40â»2.03 µM. The new compounds showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana , Tiazóis/farmacologia , Antibacterianos/síntese química , Organismos Aquáticos/química , Humanos , Imidazóis/química , Indóis/química , Concentração Inibidora 50 , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Tiazóis/síntese químicaRESUMO
Tripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34-57%). All tripentone derivatives were tested in the range of 0.1-100 µM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µM for HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The same compound was further investigated in order to study its mode of action. Results showed that it did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis. Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting its progression in S and G2/M phases.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
New thiazole nortopsentin analogs in which one of the two indole units was replaced by a naphthyl and/or 7-azaindolyl portion, were conveniently synthesized. Among these, three derivatives showed good antiproliferative activity, in particular against MCF7 cell line, with GI50 values in the micromolar range. Their cytotoxic effect on MCF7 cells was further investigated in order to elucidate their mode of action. Results showed that the three compounds act as pro-apoptotic agents inducing a clear shift of viable cells towards early apoptosis, while not exerting necrotic effects. They also caused cell cycle perturbation with significant decrease in the percentage of cells in the G0/G1 and S phases, accompanied by a concomitant percentage increase of cells in the G2/M phase, and appearance of a subG1-cell population.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HCT116 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Indóis/química , Indóis/farmacologia , Células MCF-7RESUMO
Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.
Assuntos
Proliferação de Células/efeitos dos fármacos , Piridinas/síntese química , Pirróis/síntese química , Tiazóis/síntese química , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fase G2/efeitos dos fármacos , Células HCT116/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Piridinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologiaRESUMO
A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines (~60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunction. Moreover, the compounds induced a concentration-dependent accumulation of cells in the subG0/G1phase, while confined viable cells in G2/M phase.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Indóis/síntese química , Neoplasias/tratamento farmacológico , Piridinas/síntese química , Pirróis/síntese química , Alcaloides/síntese química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Halogenação , Humanos , Imidazóis/química , Imidazóis/farmacologia , Indóis/química , Indóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metilação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Estrutura Molecular , Neoplasias/patologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Derivatives of the new ring systems bispyrido[4',3':4,5]pyrrolo[1,2-a:1',2'-d] pyrazine-6,13-dione and its deaza analogue pyrido[4'',3'':4',5']pyrrolo-[1',2':4,5]pyrazino [1,2-a]indole-6,13-dione were conveniently synthesized through a four-step sequence. Symmetrical derivatives of the former ring system were obtained through self condensation. On the other hand, condensation of 6-azaindole carboxylic acid with indole 2-carboxylic acid afforded the deaza analogue ring system. Derivatives of the title ring system were tested by the National Cancer Institute (Bethesda, MD, USA) and four of them exhibited modest activity against MCF7 (a breast cancer cell line) and/or UO-31 (a renal cancer cell line).
Assuntos
Antineoplásicos/síntese química , Compostos Heterocíclicos/síntese química , Pirazinas/síntese química , Pirróis/síntese química , Antineoplásicos/farmacologia , Ácidos Carboxílicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/química , Humanos , Células MCF-7 , Pirazinas/química , Pirróis/químicaRESUMO
Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445. From the exploration of the chemical space around the hit structure, based on iterative cycles of chemical synthesis and functional testing, the class of 6,9-dihydro-5H-pyrrolo [3,2-h]quinazolines with corrector activity was discovered. Within a series of 38 analogues, two derivatives emerged as promising candidates and used for further insight to assess the mechanism of action. Both compounds, decorated with a benzensulfonylamino group at the pyrimidine moiety, were able to generate a dose-dependent increase in CFTR function, particularly in the presence of VX-809. Half-effective concentrations (EC50) were in the single digit micromolar range and decreased in the presence of VX-809 thus indicating a synergistic interaction with class 1 correctors. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Quinazolinas , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Quinazolinas/farmacologia , Quinazolinas/química , Quinazolinas/síntese química , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Estrutura Molecular , Pirróis/farmacologia , Pirróis/química , Pirróis/síntese química , MutaçãoRESUMO
The correction of protein folding is fundamental for cellular functionality and its failure can lead to severe diseases. In this context, molecular chaperones are crucial players involved in the tricky process of assisting in protein folding, stabilization, and degradation. Chaperones, such as heat shock proteins (HSP) 90, 70, and 60, operate within complex systems, interacting with co-chaperones both to prevent protein misfolding and direct to the correct folding. Chaperone targeting drugs could represent a challenging approach for the treatment of cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CFTR gene, encoding for the CFTR chloride channel. In this review, we discuss the potential role of molecular chaperones as proteostasis modulators affecting CFTR biogenesis. In particular, we focused on HSP90 and HSP70, for their key role in CFTR folding and trafficking, as well as on HSP60 for its involvement in the inflammation process.
RESUMO
Viruses have been recognized as the etiological agents responsible for many pathological conditions ranging from asymptomatic infections to serious diseases, even leading to death. For this reason, many efforts have been made to identify selective viral targets with the aim of developing efficient therapeutic strategies, devoid of drug-resistance issues. Considering their crucial role in the viral life cycle, polymerases are very attractive targets. Among the classes of compounds explored as viral polymerases inhibitors, here we present an overview of non-nucleoside triazole-based compounds identified in the last fifteen years. Furthermore, the structure-activity relationships (SAR) of the different chemical entities are described in order to highlight the key chemical features required for the development of effective antiviral agents.
Assuntos
Triazóis , Vírus , Triazóis/farmacologia , Nucleosídeos/química , Antivirais/química , NucleotidiltransferasesRESUMO
Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3',4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC50's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC50 value of 0.10 µM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments.
Assuntos
Antineoplásicos , Tubulina (Proteína) , Humanos , Tubulina (Proteína)/metabolismo , Simulação de Acoplamento Molecular , Antineoplásicos/química , Oxazóis/farmacologia , Oxazóis/química , Proliferação de Células , Moduladores de Tubulina/farmacologia , Colchicina/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
Pyrrolomycins (PMs) are a family of naturally occurring antibiotic agents, isolated from the fermentation broth of Actinosporangium and Streptomyces species. Pursuing our studies on pyrrolomycins, we performed the total synthesis of the F-series pyrrolomycins (1-4) by microwave-assisted synthesis (MAOS), thus obtaining the title compounds in excellent yields (63-69%). Considering that there is no evidence so far of the anticancer effect of this class of compounds, we investigated PMs for their antiproliferative activity against HCT116 and MCF-7 cancer cell lines. PMs showed anticancer activity at submicromolar level with a minimal effect on normal epithelial cell line (hTERT RPE-1), and they were able to induce several morphological changes including elongated cells, cytoplasm vacuolization, long and thin filopodia as well as the appearance of tunneling nanotubes (TNTs). These data suggest that PMs could act by impairing the cell membranes and the cytoskeleton organization, with subsequent increase of ROS generation and the activation of different forms of non-apoptotic cell death.
Assuntos
Antineoplásicos , Streptomyces , Humanos , Micro-Ondas , Streptomyces/metabolismo , Fermentação , Células MCF-7RESUMO
F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1-387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1-1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.
Assuntos
Fibrose Cística , Quinolinas , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Canais de Cloreto/genética , Quinolinas/uso terapêutico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , MutaçãoRESUMO
Searching for new small molecules as photosensitizing agents, we have developed a class of twenty-five pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepines with a good substitution pattern defining a versatile synthetic pathway to approach the title ring system. All compounds were evaluated for their photocytotoxicity on a triple negative human breast cancer cell line (MDA-MB-231) in the dark and under UVA light (2.0 J/cm2). The most effective compounds exhibited a photoantiproliferative activity with IC50 values up to nanomolar ranges. Interestingly, these new developed compounds showed high selectivity towards cancerous cells with respect to non-cancerous ones. Moreover, four representative derivatives demonstrated to be phototoxic also against an additional human HER2 positive breast cancer cell line (HCC1954), and against the HER2 positive vesical cancer cell line (T24) harboring Hras mutation. Mechanistic studies performed in triple negative MDA-MB-231 cancer cells revealed the ability of the compounds to increase reactive oxygen species (ROS) production and to induce a thiol redox stress, thus triggering cancer cell death through apoptosis. Apoptotic cell death was also induced in highly aggressive and metastatic HER2 positive Hras mutated T24-treated bladder cancer cells. Overall, our data confirm that these new small photosensitizing agents may represent very promising candidates for phototherapy application against highly aggressive and resistant cancers.