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1.
Arch Pharm (Weinheim) ; : e2400536, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39239992

RESUMEN

The flavonoid chrysin is an effective vascular CaV1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1-4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to CaV1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca2+ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the CaV1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular CaV1.2 channel blockers.

2.
Int J Mol Sci ; 25(14)2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39063149

RESUMEN

Research on the energy metabolism of cancer cells is becoming a central element in oncology, and in recent decades, it has allowed us to better understand the mechanisms underlying the onset and chemoresistance of oncological pathologies. Mitochondrial bioenergetic processes, in particular, have proven to be fundamental for the survival of tumor stem cells (CSC), a subpopulation of tumor cells responsible for tumor recurrence, the onset of metastasis, and the failure of conventional anticancer therapies. Over the years, numerous natural products, in particular flavonoids, widely distributed in the plant kingdom, have been shown to interfere with tumor bioenergetics, demonstrating promising antitumor effects. Herein, the anticancer potential of Licoflavanone, a flavanone isolated from the leaves of G. glabra, was explored for the first time in breast cancer cells. The results obtained highlighted a marked antitumor activity that proved to be greater than that mediated by Glabranin or Pinocembrin, flavanones isolated from the same plant matrix. Furthermore, the investigation of Licoflavanone's effects on breast cancer energy metabolism highlighted the inhibitory activity of this natural product on tumor bioenergetics, a mechanism that could underlie its ability to reduce tumor proliferation, invasiveness, and stemness.


Asunto(s)
Neoplasias de la Mama , Metabolismo Energético , Flavanonas , Glycyrrhiza , Humanos , Flavanonas/farmacología , Flavanonas/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Metabolismo Energético/efectos de los fármacos , Femenino , Glycyrrhiza/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Células MCF-7
3.
Chimia (Aarau) ; 78(7-8): 499-512, 2024 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-39221845

RESUMEN

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.


Asunto(s)
Química Farmacéutica , Descubrimiento de Drogas , Endocannabinoides , Endocannabinoides/metabolismo , Endocannabinoides/química , Humanos , Industria Farmacéutica , Monoacilglicerol Lipasas/metabolismo , Monoacilglicerol Lipasas/antagonistas & inhibidores , Desarrollo de Medicamentos , Academia
4.
J Biol Chem ; 298(10): 102375, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35970392

RESUMEN

Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases. Schistosoma mansoni HDAC8 (SmHDAC8) is highly expressed in all life cycle stages of the parasite, and selective inhibition is required in order to avoid undesirable off-target effects in the host. Herein, by X-ray crystal structures of SmHDAC8-inhibitor complexes, biochemical and phenotypic studies, we found two schistosomicidal spiroindoline derivatives binding a novel site, next to Trp198, on the enzyme surface. We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma species, as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.


Asunto(s)
Antihelmínticos , Proteínas del Helminto , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Schistosoma mansoni , Animales , Humanos , Sitios de Unión , Proteínas del Helminto/química , Proteínas del Helminto/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Histona Desacetilasas/genética , Schistosoma mansoni/enzimología , Schistosoma mansoni/genética , Antihelmínticos/química , Antihelmínticos/farmacología , Cristalografía por Rayos X
5.
Bioorg Chem ; 131: 106326, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36563413

RESUMEN

Morin is a vasorelaxant flavonoid, whose activity is ascribable to CaV1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with CaV1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a-c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a-c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a, the series' most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a≈5c > 5b inhibited Ba2+ current through CaV1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of KCa1.1 channel currents.


Asunto(s)
Inteligencia Artificial , Bloqueadores de los Canales de Calcio , Canales de Calcio Tipo L , Flavonoides , Vasodilatación , Vasodilatadores , Animales , Ratas , Flavonoides/farmacología , Vasodilatadores/química , Vasodilatadores/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo
6.
Arch Pharm (Weinheim) ; 356(10): e2300270, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37452410

RESUMEN

Topoisomerases are ubiquitous enzymes in the human body, particularly involved in cancer development and progression. Topoisomerase I (topoI) performs DNA relaxation reactions by "controlled rotation" rather than by "strand passage." The inhibition of topoI has become a useful strategy to control cancer cell proliferation. Nowadays, different compounds have undergone clinical trials, but the search for new molecular entities is necessary and benefits from medicinal chemistry efforts. Pyrrole-based compounds emerged as promising antiproliferative agents, with particular interest in breast cancer therapy and topoI inhibition. Starting from these observations and based on the scaffold-hopping approach, we developed a small library of 1-(2-aminophenyl)pyrrole-based amides (7a-f) as new anticancer agents. Tested on a panel of cancer cell lines, 7a-f displayed the most interesting profile in MDA-MB-231 cells, where the most active compounds, 7d-f, were able to induce death by apoptosis. Direct enzymatic assays and docking simulations on the topoI active site (PDB: 1A35) revealed the inhibitory activity and potential binding site for the newly developed 1-(2-aminophenyl)pyrrole-based amides.

7.
Arch Pharm (Weinheim) ; 356(12): e2300410, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37750286

RESUMEN

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget-directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress-related conditions. We herein report the design, synthesis, and biological evaluation of the first-in-class FAAH-HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1-phenylpyrrole-based compounds 4a-j. The best-performing compounds (4c, 4f, and 4h) were tested for their neuroprotective properties in oxidative stress models, employing 1321N1 human astrocytoma cells and SHSY5 human neuronal cells. In our preliminary studies, compound 4h stood out, showing a balanced nanomolar inhibitory activity against the selected targets and outperforming the standard antioxidant N-acetylcysteine in vitro. Together with 4f, 4h was also able to protect 1321N1 cells from tert-butyl hydroperoxide or glutamate insult. Our study may provide the basis for the development of novel MTDLs targeting the ECS and epigenetic enzymes.


Asunto(s)
Inhibidores de Histona Desacetilasas , Fármacos Neuroprotectores , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Fármacos Neuroprotectores/farmacología , Relación Estructura-Actividad , Amidohidrolasas
8.
Molecules ; 28(18)2023 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-37764311

RESUMEN

Pseudomonas aeruginosa (PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth. Pyocyanin is one of the virulence factors whose production is modulated by the Pseudomonas quinolone signal (PQS) through its receptor PqsR. Different PqsR modulators have been synthesized over the years, highlighting this new powerful therapeutic strategy. Based on the promising structure of quinazolin-4(3H)-one, we developed compounds 7a-d, 8a,b, 9, 10, and 11a-f able to reduce biofilm formation and the production of virulence factors (pyocyanin and pyoverdine) at 50 µM in two PA strains responsible for CF acute and chronic infections. The developed compounds did not reduce the cell viability of IB3-1 bronchial CF cells, and computational studies confirmed the potential ability of novel compounds to act as potential Pqs system modulators.

9.
Mar Drugs ; 20(8)2022 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-36005518

RESUMEN

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.


Asunto(s)
Diterpenos , Hipertensión , Sitios de Unión , Canales de Calcio Tipo L/metabolismo , Diterpenos/farmacología , Humanos , Lactonas , Vasodilatadores/farmacología
10.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-36077415

RESUMEN

Histone deacetylases (HDACs) are epigenetic enzymes which participate in transcriptional repression and chromatin condensation mechanisms by removing the acetyl moiety from acetylated ε-amino group of histone lysines and other non-histone proteins. In recent years, HDAC8, a class I HDAC, has emerged as a promising target for different disorders, including X-linked intellectual disability, fibrotic diseases, cancer, and various neuropathological conditions. Selective HDAC8 targeting is required to limit side effects deriving from the treatment with pan-HDAC inhibitors (HDACis); thus, many endeavours have focused on the development of selective HDAC8is. In addition, polypharmacological approaches have been explored to achieve a synergistic action on multi-factorial diseases or to enhance the drug efficacy. In this frame, proteolysis-targeting chimeras (PROTACs) might be regarded as a dual-targeting approach for attaining HDAC8 proteasomal degradation. This review highlights the most relevant and recent advances relative to HDAC8 validation in various diseases, providing a snapshot of the current selective HDAC8is, with a focus on polyfunctional modulators.


Asunto(s)
Neoplasias , Proteínas Represoras , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
11.
Molecules ; 27(8)2022 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-35458759

RESUMEN

In the field of drug discovery, the nitrile group is well represented among drugs and biologically active compounds. It can form both non-covalent and covalent interactions with diverse biological targets, and it is amenable as an electrophilic warhead for covalent inhibition. The main advantage of the nitrile group as a warhead is mainly due to its milder electrophilic character relative to other more reactive groups (e.g., -CHO), reducing the possibility of unwanted reactions that would hinder the development of safe drugs, coupled to the ease of installation through different synthetic approaches. The covalent inhibition is a well-assessed design approach for serine, threonine, and cysteine protease inhibitors. The mechanism of hydrolysis of these enzymes involves the formation of a covalent acyl intermediate, and this mechanism can be exploited by introducing electrophilic warheads in order to mimic this covalent intermediate. Due to the relevant role played by the cysteine protease in the survival and replication of infective agents, spanning from viruses to protozoan parasites, we will review the most relevant and recent examples of protease inhibitors presenting a nitrile group that have been introduced to form or to facilitate the formation of a covalent bond with the catalytic cysteine active site residue.


Asunto(s)
Proteasas de Cisteína , Enfermedades Parasitarias , Cisteína/química , Inhibidores de Cisteína Proteinasa/farmacología , Descubrimiento de Drogas , Humanos , Nitrilos/farmacología
12.
Molecules ; 27(2)2022 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-35056779

RESUMEN

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 µM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.


Asunto(s)
Antiparasitarios/química , Antiparasitarios/farmacología , Benzofuranos/química , Biflavonoides/síntesis química , Chalconas/síntesis química , Indoles/química , Biflavonoides/química , Chalconas/química , Fenómenos Químicos , Técnicas de Química Sintética , Humanos , Leishmania infantum , Estructura Molecular , Relación Estructura-Actividad
13.
Pharmacol Res ; 174: 105965, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34732370

RESUMEN

Survival and expansion of malignant B cells in chronic lymphocytic leukemia (CLL) are highly dependent both on intrinsic defects in the apoptotic machinery and on the interactions with cells and soluble factors in the lymphoid microenvironment. The adaptor protein p66Shc is a negative regulator of antigen receptor signaling, chemotaxis and apoptosis whose loss in CLL B cells contributes to their extended survival and poor prognosis. Hence, the identification of compounds that restore p66Shc expression and function in malignant B cells may pave the way to a new therapeutic approach for CLL. Here we show that a novel oxazepine-based compound (OBC-1) restores p66Shc expression in primary human CLL cells by promoting JNK-dependent STAT4 activation without affecting normal B cells. Moreover, we demonstrate that the potent pro-apoptotic activity of OBC-1 in human leukemic cells directly correlates with p66Shc expression levels and is abrogated when p66Shc is genetically deleted. Preclinical testing of OBC-1 and the novel analogue OBC-2 in Eµ-TCL1 tumor-bearing mice resulted in a significantly longer overall survival and a reduction of the tumor burden in the spleen and peritoneum. Interestingly, OBCs promote leukemic cell mobilization from the spleen to the blood, which correlates with upregulation of sphingosine-1-phosphate receptor expression. In summary, our work identifies OBCs as a promising class of compounds that, by boosting p66Shc expression through the activation of the JNK/STAT4 pathway, display dual therapeutic effects for CLL intervention, namely the ability to mobilize cells from secondary lymphoid organs and a potent pro-apoptotic activity against circulating leukemic cells.


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Oxazepinas/uso terapéutico , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Ratones Transgénicos , Oxazepinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo
14.
Med Res Rev ; 40(3): 1002-1060, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31742748

RESUMEN

Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.


Asunto(s)
Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Consumo de Bebidas Alcohólicas , Antineoplásicos/farmacología , Autofagosomas/metabolismo , Biomarcadores/metabolismo , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/radioterapia , Predisposición Genética a la Enfermedad , Humanos , Lisosomas/metabolismo , Neoplasias de la Boca/radioterapia , Pronóstico , Radioterapia/métodos , Transducción de Señal , Productos de Tabaco , Virosis/complicaciones
15.
Bioorg Chem ; 102: 104067, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32663671

RESUMEN

Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease, in prevention and control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent reinfection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug perhexiline maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(-)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(-)-PHX possesses a significant activity towards S. mansoni in vitro.


Asunto(s)
Perhexilina/análogos & derivados , Schistosoma mansoni/efectos de los fármacos , Animales , Larva , Estructura Molecular , Perhexilina/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad
16.
Molecules ; 25(8)2020 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-32331470

RESUMEN

Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R2 = 0.958) and a satisfactory predictive power (Q2 = 0.822; Q2F3 = 0.894). The model was validated (r2ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.


Asunto(s)
Desarrollo de Medicamentos , Inhibidores de Histona Desacetilasas/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa , Algoritmos , Simulación por Computador , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ligandos , Estructura Molecular , Curva ROC , Reproducibilidad de los Resultados
17.
Molecules ; 25(22)2020 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-33198198

RESUMEN

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 µM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 µM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3-17.8 µM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 µM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 µM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.


Asunto(s)
Antiprotozoarios/farmacología , Arginasa/antagonistas & inhibidores , Cinamatos/farmacología , Inhibidores Enzimáticos/farmacología , Leishmania/enzimología , Proteínas Protozoarias/antagonistas & inhibidores , Animales , Sitios de Unión , Ácidos Cafeicos/química , Bovinos , Cinamatos/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Simulación de Dinámica Molecular , Conformación Proteica , Proteínas Recombinantes/química
18.
Bioorg Chem ; 89: 103020, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31185392

RESUMEN

Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.


Asunto(s)
Antimaláricos/farmacología , Materiales Biomiméticos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Férricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Compuestos Férricos/síntesis química , Compuestos Férricos/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad
19.
Exp Cell Res ; 368(2): 225-235, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29730163

RESUMEN

Mutations in MECP2 gene have been identified in more than 95% of patients with classic Rett syndrome, one of the most common neurodevelopmental disorders in females. Taking advantage of the breakthrough technology of genetic reprogramming, we investigated transcriptome changes in neurons differentiated from induced Pluripotent Stem Cells (iPSCs) derived from patients with different mutations. Profiling by RNA-seq in terminally differentiated neurons revealed a prominent GABAergic circuit disruption along with a perturbation of cytoskeleton dynamics. In particular, in mutated neurons we identified a significant decrease of acetylated α-tubulin which can be reverted by treatment with selective inhibitors of HDAC6, the main α-tubulin deacetylase. These findings contribute to shed light on Rett pathogenic mechanisms and provide hints for the treatment of Rett-associated epileptic behavior as well as for the definition of new therapeutic strategies for Rett syndrome.


Asunto(s)
Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Histona Desacetilasa 6/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatología , Tubulina (Proteína)/metabolismo , Acetilación , Diferenciación Celular/fisiología , Femenino , Humanos , Masculino
20.
Molecules ; 24(23)2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31795400

RESUMEN

Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles.


Asunto(s)
Antituberculosos , Reposicionamiento de Medicamentos , Leucocitos Mononucleares/microbiología , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis/tratamiento farmacológico , Antituberculosos/química , Antituberculosos/farmacología , Aprobación de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Tuberculosis/metabolismo , Tuberculosis/patología
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