RESUMO
The convergent and selective preparation of (Z)-monofluoroalkene-based dipeptide isosteres from functionalized fluorosulfones as a cornerstone is described. In this approach, the N-terminal amino group is introduced by a conjugate addition reaction of phthalimide onto fluorinated vinylsulfones containing α-amino-acid side chains while the C-terminal motif is linked to the fluorovinylic peptide bond mimic via the Julia-Kocienski reaction between fluorosulfones and substituted aldehydes bearing α-amino-acid side chains.
Assuntos
PeptidomiméticosRESUMO
The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R.
Assuntos
Inibidores da Colinesterase/química , Desenvolvimento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Divergent Pd-catalyzed reaction cascades with various 1,3-diynamides yielding either 2-amino-3-alkynylindoles or 2-amino-4-alkenylquinolines were established. Omitting or adding TBAF (tetrabutylammonium fluoride) to the reaction of N,N-(2-iodophenyl)(4-toluenesulfonyl)-1,3-diynamides with secondary or primary amines in the presence of KOH in THF and catalytic amounts of Pd(PPh3 )4 completely changed the outcome of the reaction. In the absence of TBAF, 2-amino-3-alkynylindoles were the sole products, while the presence of TBAF switched the product formation to 2-amino-4-alkenylquinolines. Deuterium labeling proceeded selectively at the C3 and C11 positions of the 2-amino-4-alkenylquinoline products and this suggests the unprecedented formation of [4]cumulenimines from 1,3-diynamides as reactive key intermediates.
RESUMO
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Donepezila/síntese química , Donepezila/uso terapêutico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Donepezila/química , Donepezila/farmacologia , Humanos , Modelos Moleculares , Conformação Molecular , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/uso terapêutico , EstereoisomerismoRESUMO
A reduction of various aryl, alkyl, and α,ß-unsaturated amides with phenylsilane, catalysed by a borinic acid, is reported. The unprecedented reaction was carried out under very mild conditions and led to useful amines. Furthermore, the reaction tolerates a variety of functional groups. Initial investigations implicated that an intermediate diarylhydroborane is involved in the reaction mechanism.
RESUMO
Protein-protein interactions are central to many biological processes, from intracellular communication to cytoskeleton assembly, and therefore represent an important class of targets for new therapeutics. The most common secondary structure in natural proteins is an α-helix. Small molecules seem to be attractive candidates for stabilizing or disrupting protein-protein interactions based on α-helices. In our study, we assessed the ability of oligopyridyl scaffolds to mimic the α-helical twist. The theoretical as well as experimental studies (X-ray diffraction and NMR) on conformations of bipyridines in the function of substituent and pyridine nitrogen positions were carried out. Furthermore, the experimental techniques showed that the conformations observed in bipyridines are maintained within a longer oligopyridyl scaffold (quaterpyridines). The alignment of the synthesized quaterpyridine with two methyl substituents showed that it is an α-helix foldamer; their methyl groups overlap very well with side chain positions, i and i + 3, of an ideal α-helix.
Assuntos
Biomimética/métodos , Piridinas/química , Polimerização , Estrutura Secundária de Proteína , Proteínas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-ß-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded some potent cytotoxic compounds with correlated partial antitubulin effect.
Assuntos
Colchicina/análogos & derivados , Animais , Proliferação de Células/efeitos dos fármacos , Colchicina/síntese química , Colchicina/química , Colchicina/farmacologia , Cristalografia por Raios X , Ciclização , Relação Dose-Resposta a Droga , Humanos , Células KB , Modelos Moleculares , Estrutura Molecular , Ovinos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
The pentafluorosulfanyl (-SF5 ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5 -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.
Assuntos
Química Farmacêutica , Di-Hidro-Orotato Desidrogenase , Amidas , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , HumanosRESUMO
A one-pot synthesis of various N-substituted 3-amino-thiochromanes from 4-benzyl-2-methyl thiazoline via a thiazolinium salt is described. The obtained 3-amino-thiochromanes are enantiopure, as their precursors derive from chiral 2-aminoalcohols. The reaction involves the formation of a disulfide, which subsequently takes part in an unprecedented intramolecular electrophilic aromatic substitution.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Tiazóis/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cristalografia por Raios X , Estrutura Molecular , EstereoisomerismoRESUMO
A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Isoxazóis/uso terapêutico , Receptores 5-HT4 de Serotonina/metabolismo , Doença de Alzheimer/patologia , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila/química , Donepezila/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Simulação de Acoplamento MolecularRESUMO
The first synthesis of oligonucleotides incorporating URF, a uridine modified with a difluorophosphonylated allylic ether onto the 2'-position, is described. Fluorinated homouridylates and miR-342-3p analogues are efficiently prepared. UV-melting experiments and enzymatic degradation studies indicate this new series of fluorinated oligonucleotides exhibit good and thermal metabolic stability as well as an increased lipophilicity. Comparison with oligonucleotides containing 2'- O-allyluridine instead of URF reveals improvement of these chemical properties is related to the presence of the difluoromethylphosphonate group.
Assuntos
Compostos Alílicos/química , Éteres/química , RNA/química , Temperatura , Uridina/química , Compostos Alílicos/metabolismo , Éteres/metabolismo , Conformação Molecular , Fosforilação , RNA/síntese química , RNA/metabolismo , Uridina/metabolismoRESUMO
Lipophilicity must be necessarily determined in drug discovery since this physicochemical property will directly influence the pharmacokinetics of a drug as its pharmacodynamics profile. Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant cancers. The partition coefficient (Kp) of this anticancer drug was determined by microplate assays, well adapted in drug discovery, since being rapid, and requiring only poor drug amounts. The analytical approach was performed either by UV derivative spectrophotometry after validation thanks to a set of basic, neutral and acid reference substances, or originally, by raw fluorescence spectrophotometry by taking advantage of the pyridoclax intrinsic fluorescence. Large unilamellar vesicles (LUVs) were formulated from soybean-, egg-, or dipalmitoyl-phosphatidylcholine, characterized in terms of granulometric properties, ζ potential (determined by DLS), and of phospholipid content (quantified by 1H NMR, also in presence of cholesterol). Whatever the detection method used, log Kp of pyridoclax were in the same magnitude order, and pyridoclax appeared as a lipophilic compound. It was also established that interactions between this lead and biomimetic membranes were influenced by the relative fluidity of the membranes, as confirmed by results of a liposome leakage assay.
Assuntos
Antineoplásicos/química , Piridinas/química , 1-Octanol/química , Biomimética , Fluorescência , Lipossomos , Membranas Artificiais , Fosfatidilcolinas/química , Espectrofotometria Ultravioleta , Água/químicaRESUMO
Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-xL pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyridoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-xL targeting strategies.
Assuntos
Desenho de Fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismoRESUMO
Herein we describe the drug design steps developed to increase the radical scavenging and ß-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Sequestradores de Radicais Livres/farmacologia , Alcaloides de Pirrolizidina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/síntese química , Antagonistas de Receptores Adrenérgicos alfa 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Humanos , Modelos Moleculares , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Alcaloides de Pirrolizidina/síntese química , Alcaloides de Pirrolizidina/química , Relação Estrutura-AtividadeRESUMO
This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid ß (ßA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate ßA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Compostos de Benzil/farmacologia , Agregados Proteicos/efeitos dos fármacos , Pirróis/farmacologia , Doença de Alzheimer/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Proliferação de Células , Relação Dose-Resposta a Droga , Humanos , Células KB , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.
Assuntos
Inibidores da Colinesterase/farmacologia , Piperidinas/farmacologia , Agonistas do Receptor 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Compostos de Anilina/administração & dosagem , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Inibidores da Colinesterase/química , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias , Humanos , Ligantes , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Receptores 5-HT4 de Serotonina/metabolismo , Relação Estrutura-Atividade , Testes de Toxicidade AgudaRESUMO
The purpose of the study was to investigate the degradation pathway of 5-fluorouracil (FU) in the situation of commercial formulations for clinical use, namely FU dissolved in sodium hydroxide (NaOH) solutions or Tris buffer at pH 8.5-9. Combination of data from (19)F, (1)H and (13)C NMR and in some cases MS led to the identification of 8 and 13 FU degradation products in NaOH and Tris solutions respectively. In FU NaOH solutions, the first stage of FU degradation is a stereoselective hydration of the C5-C6 double bond leading to 5,6-dihydro-5-fluoro-6-hydroxyuracil, the cis stereoisomer being predominant relative to the trans. The second stage involves either a defluorination step with formation of fluoride ion and 5-hydroxyuracil or the cleavage of the N3-C4 bond giving the two diastereoisomeric 2-fluoro-3-hydroxy-3-ureidopropanoic acids. The subsequent N1-C6 bond breakdown of these compounds releases urea and 2-fluoro-3-oxopropanoic acid (FOPA) which in turn losses easily carbon dioxide leading to the formation of fluoroacetaldehyde (Facet). The degradation pathway in FU-Tris solutions is identical, except that Tris reacts with the aldehydes FOPA and Facet to form oxazolidine adducts stable at pH 8.5 but in equilibrium with the aldehyde forms at physiological pH, whereas the high reactivity of free aldehydes leads to numerous unidentified degradation compounds all in very low amounts. The FOPA diastereoisomeric adducts react with Facet to form four diastereoisomeric fused bicyclic five-membered ring compounds. Facet and FOPA are highly cardiotoxic. In Tris formulations, they are trapped as stable oxazolidine adducts which release the free aldehydes at physiological pH thus explaining the higher cardiotoxicity of FU in Tris solutions compared to that of FU in NaOH solutions.
Assuntos
Fluoruracila/química , Soluções/química , Química Farmacêutica/métodos , Concentração de Íons de Hidrogênio , Hidrólise , Espectroscopia de Ressonância Magnética/métodos , Hidróxido de Sódio/química , Uracila/análogos & derivados , Uracila/químicaRESUMO
The coordination chemistry of a series of pro-ligands ([L¹]-[L6]) with cobalt and zinc derivatives has been studied. All complexes have been characterized by multinuclear NMR, elemental analysis, and by single-crystal X-ray diffraction studies. Polymerization of rac-lactide takes place at 130 °C in the presence of cobalt and zinc complexes to yield polymers under solvent free conditions with controlled molecular masses and narrow polydispersities.
Assuntos
Cobalto/química , Complexos de Coordenação/química , Dioxanos/química , Zinco/química , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Polimerização , Polímeros/químicaRESUMO
Nine new 17-(piperazin-1-yl)pyridin-5-yl)steroids as abiraterone analogues were synthesized. Compounds 5d and 5g showed selective activities against 17α-hydroxylase/C17,20-lyase (CYP17A1) and aromatase (CYP19), respectively. IC50 values of 5d were 5.09 and >50ï µm, whereas these values for 5g were >50 ï µm and 7.40 µm, respectively, for CYP17A1 and CYP19. Molecular modelling highlighted that the inhibitor designed to bind cytochrome P450 haem iron is a necessary condition but not the only rationale to explain inhibitory activity. These abiraterone analogues were then evaluated on hormone-independent prostate cancer cell lines DU-145 and PC-3 and on hormone-dependent breast and prostate cancer cell lines MCF-7 and LNCaP, respectively. Compounds 5e, 5g and 5i have showed potent activities only on hormone-independent prostate cancer cell lines DU-145 and PC-3 with 60-85% inhibition of both cell viability and growth at 10 nm with pro-apoptotic mechanism as illustrated in PC-3 cells by DNA ladder assay and Western blotting of Bax, Casp-3 and its substrate, the poly (ADP-ribose) polymerase. We conclude that hybrid heterocycle steroids could be good lead compounds in the drug design especially against hormone-independent prostate cancer.