RESUMO
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Assuntos
Quinase do Linfoma Anaplásico , Apoptose , Proliferação de Células , Crizotinibe , Inibidores de Proteínas Quinases , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Crizotinibe/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/patologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Masculino , Feminino , Antineoplásicos/farmacologia , Pessoa de Meia-Idade , Movimento Celular/efeitos dos fármacos , Idoso , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Células Tumorais Cultivadas , Linhagem Celular Tumoral , Proteínas de Ligação a Calmodulina , Proteínas de Membrana , Proteínas do Tecido NervosoRESUMO
Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Aldeído Desidrogenase , Linhagem Celular Tumoral , Inibidores Enzimáticos/uso terapêutico , Neoplasias Pulmonares/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Mesotelioma/metabolismo , Infiltração de Neutrófilos , Neoplasias Pleurais/patologia , Esferoides Celulares/metabolismo , Microambiente Tumoral , Retinal Desidrogenase/metabolismoRESUMO
Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.
Assuntos
Antineoplásicos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Euplotin C is a sesquiterpene of marine origin endowed with significant anti-microbial and anti-tumor properties. Despite the promising functional profile, its progress as a novel drug candidate has failed so far, due to its scarce solubility and poor stability in aqueous media, such as biological fluids. Therefore, overcoming these limits is an intriguing challenge for the scientific community. In this work, we synthesized ß-cyclodextrin-based nanosponges and investigated their use as colloidal carriers for stably complex euplotin C. Results obtained proved the ability of the carrier to include the natural compound, showing remarkable values of both loading efficiency and capacity. Moreover, it also allowed us to preserve the chemical structure of the loaded compound, which was recovered unaltered once extracted from the complex. Therefore, the use of ß-cyclodextrin-based nanosponges represents a viable option to vehiculate euplotin C, thus opening up its possible use as pharmacologically active compound.
Assuntos
Ciclodextrinas , Sesquiterpenos , beta-Ciclodextrinas , Ciclodextrinas/farmacologia , Ciclodextrinas/química , beta-Ciclodextrinas/química , Sesquiterpenos/farmacologia , SolubilidadeRESUMO
Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Deemed as poorly represented in nature, aurones have been often overlooked by researchers compared to other members of the flavonoid superfamily. However, over the past two decades, they have been reassessed by the scientific community, who are increasingly appreciating their ability to modulate several biological pathways. This review summarizes the recent literature on this class of compounds, which has been analyzed from both a chemical and a functional point of view. Original articles, reviews and editorials featured in Pubmed and Scifinder over the last twenty years have been taken into account to provide the readers with a view of the chemical strategies to obtain them, their functional properties, and their potential of technological use. The resulting comprehensive picture aims at raising the awareness of these natural derivatives as effective drug candidates, fostering the development of novel synthetic analogues.
Assuntos
Benzofuranos/síntese química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/farmacologia , Antifúngicos/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Catálise , Chalconas/química , Ciclização , Flavonoides/farmacologia , Flavonoides/normas , Humanos , Estrutura Molecular , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Iminas/química , Açúcares/química , Inibidores Enzimáticos/química , Estrutura MolecularRESUMO
A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.
Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirróis/uso terapêutico , Sulfetos/uso terapêutico , Sulfonas/uso terapêutico , Sulfóxidos/uso terapêutico , Analgésicos/síntese química , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Carragenina , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/metabolismo , Sulfonas/síntese química , Sulfonas/metabolismo , Sulfóxidos/síntese química , Sulfóxidos/metabolismoRESUMO
Diabetes is a multi-factorial disorder that should be treated with multi-effective compounds. Here we describe the access to polyhydroxylated pyrrolidines, belonging to the d-gluco and d-galacto series, through aminocyclization reactions of two differentially protected d-xylo-hexos-4-ulose derivatives. The prepared compounds proved to inhibit both alpha-glucosidase, responsible for the emergence of hyperglycemic spikes, and aldose reductase, accountable for the development of abnormalities in diabetic tissues. Accordingly, they show the dual inhibitory profile deemed as ideal for diabetes treatment. Significantly, compound 17b reduced the process of cell death and restored the physiological levels of oxidative stress when tested in the photoreceptor-like 661w cell line, thus proving to be effective in an in vitro model of diabetic retinopathy.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinas/farmacologia , alfa-Glucosidases/metabolismo , Aldeído Redutase/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Seven triterpenoid saponins were identified in methanolic extracts of seeds of the Zolfino bean landrace (Phaseolus vulgaris L.) by HPLC fractionation, revealing their ability to inhibit highly purified human recombinant aldose reductase (hAKR1B1). Six of these compounds were associated by MS analysis with the following saponins already reported in different Phaseolus vulgaris varieties: soyasaponin Ba (V), soyasaponin Bb, soyasaponin Bd (sandosaponin A), soyasaponin αg, 3-O-[R-l-rhamnopyranosyl(1 â 2)-α-d-glucopyranosyl(1 â 2)-α-d-glucuronopyranosyl]olean-12-en-22-oxo-3α,-24-diol, and soyasaponin ßg. The inhibitory activity of the collected fractions containing the above compounds was tested for hAKR1B1-dependent reduction of both l-idose and 4-hydroxynonenal, revealing that some are able to differentially inhibit the enzyme. The present work also highlights the difficulties in the search for aldose reductase differential inhibitors (ARDIs) in mixtures due to the masking effect on ARDIs exerted by the presence of conventional aldose reductase inhibitors. The possibility of differential inhibition generated by a different inhibitory model of action of molecules on different substrates undergoing transformation is also discussed.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Phaseolus/química , Saponinas/farmacologia , Sementes/química , Triterpenos/farmacologia , Aldeído Redutase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Conformação Molecular , Saponinas/química , Saponinas/isolamento & purificação , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Low-grade chronic inflammation is a key process of angiogenesis in tumour progression. We investigated whether a synthetic analogue of apigenin, the 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one (called DB103), interfered with the mechanisms involved in the angiogenic process induced by the inflammatory cytokine tumour necrosis factor (TNFα). In endothelial cells, DB103 but not apigenin reduced the TNFα-induced oxidative stress. DB103 inhibited the activation of ERK1/2 but not JNK, p38 and Akt kinases, while apigenin was not so selective because it inhibited essentially all examined kinases. Similarly, apigenin inhibited the TNFα-induced transcription factors CREB, STAT3, STAT5 and NF-κB, while DB103 acted only on NF-κB. DB103 inhibited the induced-release of angiogenic factors such as monocyte chemotactic protein-1, interleukin-6 (IL-6) and angiopoietin-2 but not IL-8, while apigenin reduced the IL-6 and IL-8 release. DB103 revealed a better ability than apigenin to modulate proangiogenic responses induced by an inflammatory microenvironment.
RESUMO
Thyroid carcinomas (TCs), the most common endocrine tumors, represent the eighth most common cancer diagnosed worldwide in both women and men. To treat these malignancies, several drugs are now available and a number of novel ones have been enrolling in clinical trials, addressing both oncogenic pathways in cancer cells and angiogenic pathways in tumor endothelial cells. However, their use is not devoid of serious toxicities and their efficacy is limited, being dependent on carcinoma typology and the occurrence of acquired resistance. Accordingly, it is time to recast therapeutic strategies against these types of tumors to get to newer and fully effective drugs. In this perspective, latest findings demonstrate that cancer stem cells (CSCs) represent a challenging target to strike. They possess core traits of self-renewal and differentiation, being resistant to the effects of chemotherapy and radiation and playing a key role in mediating metastasis. Therefore, basic molecular elements sustaining both development of thyroid cancer stem cells and their residence in the stemness condition represent a set of innovative and still unexplored targets to address. In this review, a thorough literature survey has been accomplished, to take stock of mechanisms governing thyroid carcinomas and to point out both their currently available treatments and the novel forthcoming ones. Pubmed, Scifinder and ClinicalTrials.gov were exploited as research applications and registry database, respectively. Original articles, reviews, and editorials published within the last ten years, as well as open clinical investigations in the field, were analyzed to suggest new exciting therapeutic opportunities for people affected by TCs.
Assuntos
Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , HumanosRESUMO
A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Quinazolinonas/química , Rodanina/química , Ácido Acético/química , Aldeído Redutase/metabolismo , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Rodanina/análogos & derivados , Rodanina/síntese química , Rodanina/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Tiazolidinas/química , Tiazolidinas/metabolismoRESUMO
Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.
Assuntos
Alanina/análogos & derivados , Alanina/farmacologia , Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Aldeído Redutase/metabolismo , Animais , Complicações do Diabetes/enzimologia , Complicações do Diabetes/prevenção & controle , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , RatosRESUMO
Three series of polycyclic compounds possessing either primary sulfonamide or carboxylic acid moieties as zinc-binding groups were investigated as inhibitors of four physiologically relevant CA isoforms, the cytosolic hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides reported here showed excellent inhibitory effects against isoforms hCA II, IX and XII, but no highly isoform-selective inhibition profiles. On the other hand, the carboxylates selectively inhibited hCA IX (KIs ranging between 40.8 and 92.7nM) without inhibiting significantly the other isoforms. Sulfonamides/carboxylates incorporating polycyclic ring systems such as benzothiopyranopyrimidine, pyridothiopyranopyrimidine or dihydrobenzothiopyrano[4,3-c]pyrazole may be considered as interesting candidates for exploring the design of isoform-selective CAIs with various pharmacologic applications.
Assuntos
Anidrase Carbônica I/química , Inibidores da Anidrase Carbônica/síntese química , Ácidos Carboxílicos/química , Pirazóis/química , Pirimidinas/química , Sulfonamidas/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Cinética , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
We report herein the synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl, sulfamoyl acetamides and ethyl acetates that selectively inhibit cyclooxygenase-2 (COX-2) isoform. Among the newly synthesized compounds, some of them were endowed with a good activity against COX-2 and a good selectivity COX-2/COX-1 in vitro as well as a desirable analgesic activity in vivo, proving that replacement of the ester moiety with an amide group gave access to more stable derivatives, characterized by a good COX-inhibition.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Acetatos/química , Acetatos/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Acetamidas/síntese química , Acetatos/síntese química , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Desenho de Fármacos , Humanos , Metilação , Camundongos , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Compostos de Enxofre/síntese química , Compostos de Enxofre/química , Compostos de Enxofre/farmacologiaRESUMO
An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one.
Assuntos
Solventes/química , Algoritmos , Ligantes , Modelos Moleculares , Ligação Proteica , Proteínas/química , Proteínas/metabolismoRESUMO
INTRODUCTION: The oral cavity harbors an extensive array of over 700 microorganisms, forming the most complex biome of the entire human body, with bacterial species being the most abundant. Oral diseases, e.g. periodontitis and caries, are strictly associated with bacterial dysbiosis. Porphyromonas gingivalis and Streptococcus mutans stand out among bacteria colonizing the oral cavity. AREAS COVERED: After a brief overview of the bacterial populations in the oral cavity and their roles in regulating (flora) oral cavity or causing diseases like periodontal and cariogenic pathogens, we focused our attention on P. gingivalis and S. mutans, searching for the last-5-year patents dealing with the proposal of new strategies to fight their infections. Following the PRISMA protocol, we filtered the results and analyzed over 100 applied/granted patents, to provide an in-depth insight into this R&D scenario. EXPERT OPINION: Several antibacterial proposals have been patented in this period, from both chemical - peptides and small molecules - and biological - probiotics and antibodies - sources, along with natural extracts, polymers, and drug delivery systems. Most of the inventors are from China and Korea and their studies also investigated anti-inflammatory and antioxidant effects, being beneficial to oral health through a prophylactic, protective, or curative effect.
Assuntos
Antibacterianos , Boca , Patentes como Assunto , Periodontite , Porphyromonas gingivalis , Probióticos , Streptococcus mutans , Humanos , Streptococcus mutans/efeitos dos fármacos , Porphyromonas gingivalis/efeitos dos fármacos , Boca/microbiologia , Antibacterianos/farmacologia , Probióticos/farmacologia , Animais , Periodontite/microbiologia , Periodontite/tratamento farmacológico , Cárie Dentária/microbiologia , Cárie Dentária/prevenção & controle , Saúde Bucal , Disbiose , Infecções por Bacteroidaceae/microbiologia , Infecções por Bacteroidaceae/tratamento farmacológicoRESUMO
Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.
RESUMO
INTRODUCTION: Oncogenic tyrosine kinases (TK) are enzymes that play a key role in cell growth and proliferation and their mutations can lead to uncontrolled cell growth and development of aggressive cancer. This knowledge has led to the development of new classes of drugs, Tyrosine kinase inhibitors (TKI). They target oncogenic kinases who are associated with advanced radioactive iodine (RAI) refractory TC, which is not able to uptake RAI anymore and/or still grows between consecutive treatments with Iodine 131 (I131). AREAS COVERED: Since Lenvatinib and Sorafenib approval, several other molecular inhibitors have been studied and then introduced for the treatment of aggressive and refractory thyroid cancer (TC), and, although the development of adverse effects or tumor resistance mechanisms, more and more compounds are still under investigation. The literature search was executed in PubMed and ClinicalTrials.gov to identify relevant articles and clinical trials published until December 2023. EXPERT OPINION: In the context of clinical trials, driven by the presence of specific molecular mutations or even in the absence of both conditions, systemic therapy TKIs are valuable weapons to be used in patients affected by aggressive forms of TC, waiting for further expansion of the treatment landscape with more efficacious and safer drugs.