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1.
Molecules ; 29(9)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38731618

RESUMEN

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.


Asunto(s)
Indoles , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/química
2.
J Med Chem ; 67(1): 17-37, 2024 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-38113353

RESUMEN

Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.


Asunto(s)
Cardiopatías , Receptores de GABA , Humanos , Receptores de GABA/metabolismo , Membranas Mitocondriales/metabolismo , Cardiopatías/tratamiento farmacológico , Cardiopatías/metabolismo , Ligandos
3.
Pharmaceuticals (Basel) ; 16(7)2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37513909

RESUMEN

In recent years, indolylglyoxylamide-based derivatives have received much attention due to their application in drug design and discovery, leading to the development of a wide array of compounds that have shown a variety of pharmacological activities. Combining the indole nucleus, already validated as a "privileged structure," with the glyoxylamide function allowed for an excellent template to be obtained that is suitable to a great number of structural modifications aimed at permitting interaction with specific molecular targets and producing desirable therapeutic effects. The present review provides insight into how medicinal chemists have elegantly exploited the indolylglyoxylamide moiety to obtain potentially useful drugs, with a particular focus on compounds exhibiting activity in in vivo models or reaching clinical trials. All in all, this information provides exciting new perspectives on existing data that can be useful in further design of indolylglyoxylamide-based molecules with interesting pharmacological profiles. The aim of this report is to present an update of collection data dealing with the employment of this moiety in the rational design of compounds that are able to interact with a specific target, referring to the last 20 years.

4.
Eur J Med Chem ; 256: 115446, 2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37182332

RESUMEN

BRAF represents one of the most frequently mutated protein kinase genes and BRAFV600E mutation may be found in many types of cancer, including hairy cell leukemia (HCL), anaplastic thyroid cancer (ATC), colorectal cancer and melanoma. Herein, a fluorescent probe, based on the structure of the highly specific BRAFV600E inhibitor Vemurafenib (Vem, 1) and featuring the NIR fluorophore cyanine-5 (Cy5), was straightforwardly synthesized and characterized (Vem-L-Cy5, 3), showing promising spectroscopic properties. Biological validation in BRAFV600E-mutated cancer cells evidenced the ability of 3 to penetrate inside the cells, specifically binding to its elective target BRAFV600E with high affinity, and inhibiting MEK phosphorylation and cell growth with a potency comparable to that of native Vem 1. Taken together, these data highlight Vem-L-Cy5 3 as a useful tool to probe BRAFV600E mutation in cancer cells, and suitable to acquire precious insights for future developments of more informed BRAF inhibitors-centered therapeutic strategies.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Vemurafenib/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Línea Celular Tumoral
5.
Molecules ; 28(6)2023 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-36985576

RESUMEN

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor, with a poor prognosis and the highest mortality rate. Currently, GBM therapy consists of surgical resection of the tumor, radiotherapy, and adjuvant chemotherapy with temozolomide. Consistently, there are poor treatment options and only modest anticancer efficacy is achieved; therefore, there is still a need for the development of new effective therapies for GBM. Indole is considered one of the most privileged scaffolds in heterocyclic chemistry, so it may serve as an effective probe for the development of new drug candidates against challenging diseases, including GBM. This review analyzes the therapeutic benefit and clinical development of novel indole-based derivatives investigated as promising anti-GBM agents. The existing indole-based compounds which are in the pre-clinical and clinical stages of development against GBM are reported, with particular reference to the most recent advances between 2013 and 2022. The main mechanisms of action underlying their anti-GBM efficacy, such as protein kinase, tubulin and p53 pathway inhibition, are also discussed. The final goal is to pave the way for medicinal chemists in the future design and development of novel effective indole-based anti-GBM agents.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/metabolismo , Temozolomida/farmacología , Indoles/farmacología , Indoles/uso terapéutico , Neoplasias Encefálicas/metabolismo
6.
Biomedicines ; 10(11)2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-36428499

RESUMEN

Topoisomerase (Topo) inhibitors have long been known as clinically effective drugs, while G-quadruplex (G4)-targeting compounds are emerging as a promising new strategy to target tumor cells and could support personalized treatment approaches in the near future. G-quadruplex (G4) is a secondary four-stranded DNA helical structure constituted of guanine-rich nucleic acids, and its stabilization impairs telomere replication, triggering the activation of several protein factors at telomere levels, including Topos. Thus, the pharmacological intervention through the simultaneous G4 stabilization and Topos inhibition offers a new opportunity to achieve greater antiproliferative activity and circumvent cellular insensitivity and resistance. In this line, dual ligands targeting both Topos and G4 emerge as innovative, efficient agents in cancer therapy. Although the research in this field is still limited, to date, some chemotypes have been identified, showing this dual activity and an interesting pharmacological profile. This paper reviews the available literature on dual Topo inhibitors/G4 stabilizing agents, with particular attention to the structure-activity relationship studies correlating the dual activity with the cytotoxic activity.

7.
ACS Chem Neurosci ; 13(22): 3188-3197, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36300862

RESUMEN

The 18 kDa translocator protein (TSPO) is predominantly located in the mitochondrial outer membrane, playing an important role in steroidogenesis, inflammation, survival, and cell proliferation. Its expression in the CNS, and mainly in glial cells, is upregulated in neuropathologies and brain injury. In this study, the potential of targeting TSPO for the therapeutic treatment of inflammatory-based retinal neurodegeneration was evaluated by means of an in vitro model of lipopolysaccharide (LPS)-induced degeneration in 661 W cells, a photoreceptor-like cell line. After the assessment of the expression of TSPO in 661W cells, which, to the best of our knowledge, was never investigated so far, the anti-inflammatory and cytoprotective effects of a number of known TSPO ligands, belonging to the class of N,N-dialkyl-2-arylindol-3-ylglyoxylamides (PIGAs), were evaluated, using the classic TSPO ligand PK11195 as the reference standard. All tested PIGAs showed the ability to modulate the inflammatory and apoptotic processes in 661 W photoreceptor-like cells and to reduce LPS-driven cellular cytotoxicity. The protective effect of PIGAs was, in all cases, reduced by cotreatment with the pregnenolone synthesis inhibitor SU-10603, suggesting the involvement of neurosteroids in the protective mechanism. As inflammatory processes play a crucial role in the retinal neurodegenerative disease progression toward photoreceptors' death and complete blindness, targeting TSPO might represent a successful strategy to slow down this degenerative process that may lead to the inexorable loss of vision.


Asunto(s)
Enfermedades Neurodegenerativas , Degeneración Retiniana , Humanos , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/patología , Lipopolisacáridos/farmacología , Receptores de GABA/metabolismo , Inflamación/metabolismo , Apoptosis , Proteínas Portadoras , Ligandos
8.
Arch Pharm (Weinheim) ; 355(11): e2200295, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35904260

RESUMEN

A series of novel 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine (BIT) derivatives were designed and synthesized. In vitro antiproliferative activity was detected toward two human colorectal adenocarcinoma cell lines (CaCo-2 and HT-29) and one human dermal microvascular endothelial cell line (HMVEC-d). The most active compounds, namely 2-4 and 8, were further investigated to clarify the mechanism behind their biological activity. Through immunofluorescence assay, we identified the target of these molecules to be the microtubule cytoskeleton with subsequent formation of dense microtubule accumulation, particularly at the periphery of the cancer cells, as observed in paclitaxel-treated cells. Overall, these results highlight BIT derivatives as robust and feasible candidates deserving to be further developed in the search for novel potent antiproliferative microtubule-targeting agents.


Asunto(s)
Antineoplásicos , Triazinas , Humanos , Triazinas/farmacología , Relación Estructura-Actividad , Células CACO-2 , Proliferación Celular , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Estructura Molecular
9.
Molecules ; 27(8)2022 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-35458743

RESUMEN

Carbonic anhydrases (CAs) are a family of ubiquitous metal enzymes catalyzing the reversible conversion of CO2 and H2O to HCO3- with the release of a proton. They play an important role in pH regulation and in the balance of body fluids and are involved in several functions such as homeostasis regulation and cellular respiration. For these reasons, they have been studied as targets for the development of agents for treating several pathologies. CA inhibitors have been used in therapy for a long time, especially as diuretics and for the treatment of glaucoma, and are being investigated for application in other pathologies including obesity, cancer, and epilepsy. On the contrary, CAs activators are still poorly studied. They are proposed to act as additional (other than histidine) proton shuttles in the rate-limiting step of the CA catalytic cycle, which is the generation of the active hydroxylated enzyme. Recent studies highlight the involvement of CAs activation in brain processes essential for the transmission of neuronal signals, suggesting CAs activation might represent a potential therapeutic approach for the treatment of Alzheimer's disease and other conditions characterized by memory impairment and cognitive problems. Actually, some compounds able to activate CAs have been identified and proposed to potentially resolve problems related to neurodegeneration. This review reports on the primary literature regarding the potential of CA activators for treating neurodegeneration-related diseases.


Asunto(s)
Anhidrasas Carbónicas , Activadores de Enzimas , Epilepsia , Enfermedades Neurodegenerativas , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasas Carbónicas/química , Catálisis , Activadores de Enzimas/uso terapéutico , Epilepsia/tratamiento farmacológico , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Protones
10.
Mini Rev Med Chem ; 22(14): 1816-1827, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35176979

RESUMEN

In 2018, James Allison and Tasuku Honjo received the Nobel Prize in physiology or medicine to discover tumor therapy by inhibition of negative immune regulation. Immunotherapy stimulates T-cells to fight cancer cells by blocking different immune checkpoint pathways. The interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 (Programmed cell death ligand 1) is one of the main pathways. Of note, interfering with this pathway is already exploited in clinical cancer therapy, demonstrating that it is one of the key factors involved in the immune escape mechanism of cancer. The development of monoclonal antibodies (mAbs) that possess the ability to inhibit the interactions between PD-1/PD-L1 has radically made the difference in cancer immunotherapy. Yet, due to the many drawbacks of this therapy, the research shifted its efforts towards the development of novel small molecules. This may constitute hope and an arduous challenge in fighting cancer. This paper reviews the recent primary literature concerning the development of novel small molecules able to block the interaction between PD-1 and its ligand PD-L1.


Asunto(s)
Antineoplásicos Inmunológicos , Neoplasias , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Humanos , Inmunoterapia , Ligandos , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores
11.
Molecules ; 26(24)2021 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-34946600

RESUMEN

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.


Asunto(s)
Anilidas , Benzamidas , Inhibidores Enzimáticos , Proteínas de Microfilamentos , Oxidorreductasas , Bibliotecas de Moléculas Pequeñas , Humanos , Anilidas/química , Anilidas/farmacología , Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteínas de Microfilamentos/antagonistas & inhibidores , Proteínas de Microfilamentos/metabolismo , Estructura Molecular , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
13.
J Enzyme Inhib Med Chem ; 36(1): 1874-1883, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34340614

RESUMEN

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.


Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Biología Computacional/métodos , Isoenzimas/antagonistas & inhibidores , Quinazolinas/química , Sulfonamidas/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Evaluación Preclínica de Medicamentos , Simulación del Acoplamiento Molecular , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-Actividad , Sulfonamidas/química
14.
J Enzyme Inhib Med Chem ; 36(1): 1783-1797, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34340630

RESUMEN

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.


Asunto(s)
Anhidrasas Carbónicas/efectos de los fármacos , Activadores de Enzimas/farmacología , Indoles/farmacología , Isoenzimas/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Espectroscopía de Resonancia Magnética con Carbono-13 , Anhidrasas Carbónicas/metabolismo , Supervivencia Celular/efectos de los fármacos , Activación Enzimática , Activadores de Enzimas/química , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Indoles/química , Isoenzimas/metabolismo , Microglía/citología , Microglía/efectos de los fármacos , Modelos Moleculares , Espectroscopía de Protones por Resonancia Magnética , Especificidad por Sustrato
15.
Eur J Med Chem ; 220: 113490, 2021 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-33975138

RESUMEN

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators. In this contribution, starting from our previous studies, we describe the synthesis of a set of new bicyclic tetrahydroindazoles featuring a secondary sulfonamide. Biological evaluation of the inhibitory activity against the hCA I, II, IV, and IX isoforms allowed drawing a structure-activity relationship profile that was rationalized through theoretical studies. This allowed dissecting the new molecules into the single portions influencing the zinc chelation properties and the selectivity profile thereby offering a new platform for the discovery of new isotype selective CA inhibitors.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Indazoles/farmacología , Sulfonamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
16.
J Med Chem ; 64(7): 3508-3545, 2021 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-33764065

RESUMEN

Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery. After a brief analysis of its physical-chemical features and synthetic procedures to obtain it, α-ketoamide-based classes of compounds are reported according to the application of this motif as either a nonreactive or reactive moiety. The goal is to highlight those aspects that may be useful to understanding the perspectives of employing the α-ketoamide moiety in the rational design of compounds able to interact with a specific target.


Asunto(s)
Amidas/farmacología , Química Farmacéutica/métodos , Cetonas/farmacología , Amidas/química , Animales , Línea Celular Tumoral , Humanos , Cetonas/química
17.
J Enzyme Inhib Med Chem ; 36(1): 286-294, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33334192

RESUMEN

Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR.


Asunto(s)
Indoles/farmacología , Receptor de Adenosina A2B/metabolismo , Regulación Alostérica/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Células Madre Mesenquimatosas/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad
18.
Eur J Med Chem ; 209: 112924, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33081988

RESUMEN

The Translocator Protein 18 kDa (TSPO) has been discovered in 1977 as an alternative binding site for the benzodiazepine diazepam. It is an evolutionary well-conserved and tryptophan-rich 169-amino acids protein with five alpha helical transmembrane domains stretching the outer mitochondrial membrane, with the carboxyl-terminus in the cytosol and a short amino-terminus in the intermembrane space of mitochondrion. At this level, together with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT), it forms the mitochondrial permeability transition pore (MPTP). TSPO expression is ubiquitary, with higher levels in steroid producing tissues; in the central nervous system, it is mainly expressed in glial cells and in neurons. TSPO is implicated in a variety of fundamental cellular processes including steroidogenesis, heme biosynthesis, mitochondrial respiration, mitochondrial membrane potential, cell proliferation and differentiation, cell life/death balance, oxidative stress. Altered TSPO expression has been found in some pathological conditions. In particular, high TSPO expression levels have been documented in cancer, neuroinflammation, and brain injury. Conversely, low TSPO expression levels have been evidenced in anxiety disorders. Therefore, TSPO is not only an interesting drug target for therapeutic purpose (anticonvulsant, anxiolytic, etc.), but also a valid diagnostic marker of related-diseases detectable by fluorescent or radiolabeled ligands. The aim of this report is to present an update of previous reviews dealing with the medicinal chemistry of TSPO and to highlight the most outstanding advances in the development of TSPO ligands as potential therapeutic or diagnostic tools, especially referring to the last five years.


Asunto(s)
Ansiolíticos/química , Anticonvulsivantes/química , Benzodiazepinas/química , Diazepam/química , Receptores de GABA/metabolismo , Secuencia de Aminoácidos , Animales , Ansiolíticos/farmacología , Anticonvulsivantes/farmacología , Apoptosis/efectos de los fármacos , Bencimidazoles/química , Proliferación Celular/efectos de los fármacos , Humanos , Imidazoles/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Membranas Mitocondriales/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Estrés Oxidativo/efectos de los fármacos , Unión Proteica , Piridinas/química , Quinolinas/química , Receptores de GABA/genética , Relación Estructura-Actividad , Canales Aniónicos Dependientes del Voltaje/metabolismo
19.
Eur J Pharm Sci ; 156: 105594, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33059042

RESUMEN

DNA Topoisomerases (Topos) are ubiquitous nuclear enzymes involved in regulating the topological state of DNA and, in eukaryotic organisms, Topos can be classified into two structurally and functionally different main classes: TopoI and TopoII. Both these enzymes proved to be excellent targets of clinically significant classes of anticancer drugs. Actually, TopoI or II inhibitors show considerable wide spectrum antitumor activities, an important feature to be included in many chemotherapeutic protocols. Despite their clinical efficacy, the use of inhibitors targeting only one of the two enzymes can increase the levels of the other one, favouring the onset of unwanted phenomena such as drug resistance. Therefore, targeting both TopoI and TopoII can reduce the probability of developing resistance, as well as side effects thanks to the use of lower doses, given the synergistic effect of the dual activity. Moreover, since drug resistance is also due to DNA repair systems such as tyrosyl-DNA phosphodiesterases I and II, inhibiting Topoisomerases concomitantly to Tyrosyl-DNA phosphodiesterase enzymes could allow more efficient and safe drugs. This review represents an update of previous works reporting about dual TopoI and TopoII inhibitors, but also an overview of the new strategy regarding the development of derivatives able to simultaneously inhibit Topo and TDP enzymes, with particular attention to structure-affinity relationship studies. The newly collected derivatives are described focusing attention on their chemical structures and their biological profiles. The final aim is to highlight the structural requirements necessary for the development of potent multiple modulators of these targets, thus providing new potential antitumor agents for the clinical usage.


Asunto(s)
Antineoplásicos , ADN-Topoisomerasas de Tipo I , Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN , Hidrolasas Diéster Fosfóricas , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/farmacología
20.
Eur J Pharm Sci ; 149: 105337, 2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32311457

RESUMEN

The oncogene KRAS is involved in the pathogenesis of many tumors such as pancreatic, lung and colorectal cancers, thereby representing a relevant target for the treatment of these diseases. The KRAS P1 promoter contains a nuclease hypersensitive, guanine-rich sequence able to fold into a G-quadruplex motif (G4). The stabilization of this G4 structure by small molecules is emerging as a feasible approach to downregulate KRAS expression. Here, a set of novel stabilizing molecules was identified through a virtual screening campaign on the NMR structure of the 22-mer KRAS G4. The most promising hits were then submitted to structure-activity relationships studies which allowed improving their binding affinity and selectivity over double helix DNA and different G4 topologies. The best derivative (19) underwent fluorescence titration experiments and further computational studies to disclose its binding mechanism to KRAS G4. Finally, biological assays showed that this compound is capable to reduce the viability of colorectal cancer cells in which mutated KRAS acts as a driver oncogene. Thus, 19 might represent the prototype of a new class of drugs for the treatment of tumors that, expressing mutated forms of KRAS, are refractory to current therapeutic regimens.

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