RESUMO
A series of novel tricyclic matrinic derivatives with 11-adamantyl substitution were designed, synthesized, and evaluated for their activities against Influenza A H3N2 virus, based on the privileged structure strategy. Structure-activity relationship (SAR) analysis indicated that the introduction of an 11-adamantyl might be helpful for the potency. Among them, compounds 9f and 9j exhibited the promising anti-H3N2 activities with IC50 values of 7.2 µM and 10.2 µM, respectively, better than that of lead 1. Their activities were further confirmed at the protein level. Moreover, compound 9f displayed a high pharmacokinetic (PK) stability profile in whole blood and a safety profile in vivo. In primary mechanism, compound 9f could inhibit the virus replication cycle at early stage by targeting M2 protein, consistent with that of the parent amantadine. This study provided powerful information for further strategic optimization to develop these compounds into a new class of anti-influenza agents.
Assuntos
Amantadina/síntese química , Amantadina/uso terapêutico , Antivirais/síntese química , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Amantadina/administração & dosagem , Animais , Antivirais/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Feminino , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Células Madin Darby de Rim Canino , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Adamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths. METHODS: Symmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers. The inhibitory activity of the compounds was studied on two viroporins: the influenza virus M2 protein, expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique, and the hepatitis C virus (HCV) p7 channels for five different genotypes (1a, 1b, 2a, 3a, and 4a) expressed in HEK293 cells using whole-cell patch-clamp recording techniques. RESULTS: Upon testing on M2 protein, dimeric compounds showed significantly lower inhibitory activity relative to the monomeric amantadine. The lack of channel blockage of the dimeric amantadine and rimantadine analogs against M2 wild type and M2-S31N mutant was consistent with previously proposed drug-binding mechanisms and further confirmed that the pore-binding model is the pharmacologically relevant drug-binding model. On the other hand, these dimers showed similar potency to their respective monomeric analogs when tested on p7 protein in HCV genotypes 1a, 1b, and 4a while being 700-fold and 150-fold more potent than amantadine in genotypes 2a and 3a, respectively. An amino group appears to be important for inhibiting the ion-channel activity of p7 protein in genotype 2a, while its importance was minimal in all other genotypes. CONCLUSION: Symmetric dimeric adamantanes can be considered a prospective class of p7 inhibitors that are able to address the differences in adamantane sensitivity among the various genotypes of HCV.
Assuntos
Adamantano/farmacologia , Amantadina/farmacologia , Antivirais/farmacologia , Rimantadina/farmacologia , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Adamantano/síntese química , Adamantano/química , Amantadina/síntese química , Amantadina/química , Antivirais/síntese química , Antivirais/química , Células Cultivadas , Desenho de Fármacos , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Rimantadina/síntese química , Rimantadina/química , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismoRESUMO
Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC50 = 0.081 ± 0.003 µM), 6a (IC50 = 0.0022 ± 0.0002 µM), 9e (IC50 = 0.0250 ± 0.0007 µM) and 12d (IC50 = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC50 = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.
Assuntos
Inibidores Enzimáticos/química , Sequestradores de Radicais Livres/química , Sulfonamidas/química , Urease/antagonistas & inibidores , Amantadina/análogos & derivados , Amantadina/síntese química , Amantadina/química , Ciprofloxacina/análogos & derivados , Ciprofloxacina/síntese química , Ciprofloxacina/química , Inibidores Enzimáticos/síntese química , Fabaceae/química , Fabaceae/enzimologia , Sequestradores de Radicais Livres/síntese química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfadiazina/análogos & derivados , Sulfadiazina/síntese química , Sulfadiazina/química , Sulfonamidas/síntese química , Urease/químicaRESUMO
Heating a mixture of Nd(NO3)3·6H2O, KCl, Q[10] and Q[5] in HCl for 10 min affords the inclusion complex {NdQ[5]K@Q[10](H2O)4}·4NO3·20H2O. The structure of the inclusion complex has been investigated by single crystal X-ray diffraction and by X-ray Photoelectron spectroscopy (XPS).
Assuntos
Amantadina/análogos & derivados , Amantadina/química , Complexos de Coordenação/química , Neodímio/química , Amantadina/síntese química , Cristalografia por Raios X/métodos , Estrutura Molecular , Espectroscopia Fotoeletrônica/métodos , Difração de Raios X/métodosRESUMO
Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.
Assuntos
Amantadina/análogos & derivados , Ácidos Carboxílicos/síntese química , Técnicas de Química Sintética/instrumentação , Amantadina/síntese química , Amantadina/química , Ácidos Carboxílicos/química , Desenho de EquipamentoRESUMO
Platinum-based chemotherapeutic drugs such as cisplatin, carboplatin and oxaliplatin are widely applied for the treatment of various types of tumours. Over the last few decades, a large variety of Pt(II) and Pt(IV) complexes have been developed to improve the applicability in a wider spectrum of cancers, increase their therapeutic window and reduce the dose-limiting side effects. Photodynamic therapy (PDT), which is the administration of a photosensitiser followed by visible light activation, is a promising route to avoid damage to healthy cells and the surrounding tissue. Transition metal complexes as photochemotherapeutic agents are an attractive option for further development in the field of photoactivated chemotherapy (PACT). These complexes exhibit different numbers and types of excited states which are easily accessible upon light irradiation, subsequently giving rise to the formation of various photoproducts that can enable a distinct mode of action. Platinum-diazido complexes are promising candidates for PACT due to the low cytotoxicity when irradiated with visible light. This review summarises the mode of action of current platinum anticancer drugs with cisplatin as a lead example and the development of non-conventional Pt(II) complexes. Background information regarding PDT the photophysical and photochemical properties of metal complexes is provided, as well as notable examples of photoactivated metal complexes with biological activity. Particular emphasis is placed on recent developments on platinum photoactivated drugs.
Assuntos
Antineoplásicos/química , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/química , Fármacos Fotossensibilizantes/química , Amantadina/análogos & derivados , Amantadina/síntese química , Amantadina/química , Amantadina/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Cisplatino/síntese química , Cisplatino/química , Cisplatino/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Luz , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
The LiCl-mediated Mg-insertion in the presence of ZnCl2 allows an efficient synthesis of adamantylzinc reagents starting from the corresponding functionalized tertiary bromides. The highly reactive adamantylzinc species readily undergo a broad variety of functionalizations such as Negishi cross-couplings, Cu(I)-catalyzed acylations and allylations, and 1,4-addition reactions leading to the expected products in excellent yields. Furthermore, the adamantyl moiety could be introduced as α-substituent in terthiophene, increasing its solubility due to the higher lipophilicity and the prevention of π-stacking.
Assuntos
Amantadina/síntese química , Cloretos/química , Indicadores e Reagentes/síntese química , Cloreto de Lítio/química , Magnésio/química , Compostos de Zinco/química , Amantadina/química , Catálise , Indicadores e Reagentes/química , Estrutura Molecular , EstereoisomerismoRESUMO
A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 µM for hAChE and an IC50 value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amantadina/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Dimerização , Modelos Moleculares , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Amantadina/síntese química , Amantadina/química , Amantadina/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Ensaios Enzimáticos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Padrões de Referência , Tacrina/síntese química , Tacrina/química , Tacrina/farmacologia , Tacrina/uso terapêutico , Tioureia/químicaRESUMO
The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.
Assuntos
Antivirais/química , Antivirais/farmacologia , Genes Fúngicos , Vírus da Influenza A/química , Vírus da Influenza A/genética , Mutação , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Amantadina/análogos & derivados , Amantadina/síntese química , Amantadina/química , Amantadina/farmacologia , Antivirais/síntese química , Sítios de Ligação , Desenho de Fármacos , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A/efeitos dos fármacos , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Proteínas da Matriz Viral/antagonistas & inibidoresRESUMO
Grafting cadmium sulfide onto alumina induces a small bandgap widening and a more significant lifetime variation of the light generated charge carriers from 0.76 microseconds measured for pristine CdS to 0.75, 0.86, and 1.20 microseconds found for CdS/Al(2)O(3) containing 30, 20, and 9% of CdS, respectively. The quasi-Fermi level of electrons of -0.42 V (NHE) is not significantly changed. These alumina grafted semiconductor photocatalysts enable the linear addition of cyclopentene, cyclohexene, and α-pinene to N-adamantylimines affording novel homoallyladamantylamines in isolated yields of 21-85% through a regioselective C-C heterocoupling of intermediate allyl and α-aminobenzyl radicals. As by-products hydrodimers of the imine are formed by C-C homocoupling of the benzylic radicals. Different from heterocoupling, the homocoupling is a stereospecific process directed by the nature of the olefin employed in the reaction.
Assuntos
Óxido de Alumínio/química , Amantadina/química , Compostos de Cádmio/química , Cicloparafinas/química , Iminas/química , Sulfetos/química , Amantadina/síntese química , Catálise , Cristalografia por Raios X , Luz , Conformação Molecular , EstereoisomerismoRESUMO
A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-D-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3-propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8-oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Amantadina/síntese química , Amantadina/química , Amantadina/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Ligantes , Masculino , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
The amino acid and peptide derivatives of 1-adamantane carboxylic acid and rimantadine (18 compounds) have been first synthesized and investigated for their activity against influenza A virus (H1N1, H1N1v). In a series of obtained adamantine derivatives, some compounds have been found to be able to inhibit rimantadine-resistant influenza A virus strains. Thus, the antiviral properties of rimantadine can be restored.
Assuntos
Adamantano/análogos & derivados , Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Rimantadina/farmacologia , Adamantano/síntese química , Adamantano/farmacologia , Adamantano/uso terapêutico , Amantadina/análogos & derivados , Amantadina/síntese química , Amantadina/farmacologia , Amantadina/uso terapêutico , Antivirais/síntese química , Antivirais/uso terapêutico , Humanos , Rimantadina/análogos & derivados , Rimantadina/síntese química , Rimantadina/uso terapêuticoRESUMO
Influenza is a major threat to millions of people worldwide. Vaccines and antiviral agents are two main options available to reduce the impact of the influenza virus, while anti-influenza agents are the most effective means to prevent the transmission of the highly contagious virus and to treat the epidemics of disease. At present, four anti-influenza agents have been approved by the FDA for the treatment of influenza, including two M2 protein ion channel inhibitors-amantadine and rimantadine and two neuraminidase inhibitors-zanamivir and oseltamivir. Arbidol hydrochloride, launched in Russia, is a potent inhibitor of influenza virus, too. Neuraminidase inhibitors could be classified generally by structure into six different kinds: sialic acid derivatives, benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. In this paper, recent progress in the research of the action mechanisms and structure-activity relationships of these anti-influenza virus agents were reviewed.
Assuntos
Antivirais , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Proteínas da Matriz Viral/antagonistas & inibidores , Ácidos Carbocíclicos , Amantadina/síntese química , Amantadina/química , Amantadina/farmacologia , Amantadina/uso terapêutico , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Ciclopentanos/síntese química , Ciclopentanos/química , Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Guanidinas/síntese química , Guanidinas/química , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/síntese química , Neuraminidase/química , Neuraminidase/farmacologia , Neuraminidase/uso terapêutico , Oseltamivir/síntese química , Oseltamivir/química , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Rimantadina/síntese química , Rimantadina/química , Rimantadina/farmacologia , Rimantadina/uso terapêutico , Relação Estrutura-Atividade , Proteínas da Matriz Viral/síntese química , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/farmacologia , Proteínas da Matriz Viral/uso terapêutico , Zanamivir/síntese química , Zanamivir/química , Zanamivir/farmacologia , Zanamivir/uso terapêuticoRESUMO
The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopamine uptake were also assessed.
Assuntos
Amantadina/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Amantadina/síntese química , Amantadina/farmacologia , Animais , Células Cultivadas , Cães , Dopamina/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Concentração Inibidora 50 , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Adamantanopyrrolidines 8, 9 and 10, adamantanopyrrolidines 16 and 18, adamantanoxazolone 20, adamantanopyrazolone 23, adamantanopyrazolothione 24 and adamantanocyclopentanamine 32 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. Pyrrolidine 16 proved to be the most active of the compounds tested against influenza A virus, being 4-fold more active than amantadine, equipotent to rimantadine and 19-fold more potent than ribavirin. Oxazolone 20 showed significant trypanocidal activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being approximately 3 times more potent than rimantadine and almost 50-fold more active than amantadine.
Assuntos
Amantadina/síntese química , Antivirais/síntese química , Desenho de Fármacos , Rimantadina/síntese química , Tripanossomicidas/síntese química , Amantadina/química , Amantadina/uso terapêutico , Animais , Antivirais/química , Antivirais/uso terapêutico , Vírus da Influenza A Subtipo H3N2/patogenicidade , Infecções por Orthomyxoviridae/tratamento farmacológico , Ribavirina/uso terapêutico , Rimantadina/química , Rimantadina/uso terapêutico , Suínos , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Proteínas da Matriz Viral/metabolismoRESUMO
Seven novel derivatives of aminoadamantane with 1-aminosubstituted group were synthesized from amantadine or memantine individually in order to find new neuroprotective agent. Six of them are amides of two precursors, one is a 1-amino derivative of memantine substituted with 2-hydroxy propyl. Their chemical structures were confirmed by 1H NMR and HRMS. The neuroprotective activity in vitro was evaluated primarily with 500 micromol x L(-1) glutamate damaged SY5Y cell by measurement of MTT metabolic rate and LDH leakage rate. Glutamate reduced MTT metabolic rate, but increased LDH leakage rate significantly. The addition of new derivatives elevated the MTT value with their certain concentration, reduced cell death rate. Especially as for 3d and 4c, they fully normalized LDH leakage rate with concentration of 20 micromol x L(-1) during LDH measurement. These data indicated that 3d and 4c have significant protective effect on nerve cell against glutamate injury, deserved to be further tested and maybe helpful for treatment of neurodegenerative disease.
Assuntos
Amantadina/análogos & derivados , Amantadina/síntese química , Neuroblastoma/patologia , Fármacos Neuroprotetores/síntese química , Amantadina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Glutâmico/toxicidade , Humanos , L-Lactato Desidrogenase/metabolismo , Memantina/química , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
Procedure of the synthesis is described for new platinum(IV) drug LA-12 [(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)]. The X-ray diffraction analysis shows that the structure is created by molecules with octahedral arrangement of ligands around a platinum atom and contains one H(2)O molecule that is not a part of the coordination sphere of platinum. This new drug is more reactive with glutathione than cisplatin and is lacking cross-resistance with cisplatin as proven on the panel of cancer cell lines.
Assuntos
Amantadina/química , Amantadina/síntese química , Antineoplásicos/síntese química , Compostos Organoplatínicos/síntese química , Amantadina/análogos & derivados , Amantadina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel series of indole-2-carboxylate analogues of GV 150526 (1) in which the terminal phenyl ring belonging to the side chain present in the position C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindole-2 -carboxylic acid 6b and 3-[2-(norbornylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.
Assuntos
Amantadina/análogos & derivados , Antagonistas de Aminoácidos Excitatórios/síntese química , Indóis/síntese química , Norbornanos/síntese química , Receptores de Glicina/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Amantadina/síntese química , Amantadina/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Indóis/farmacologia , Ligantes , Camundongos , Modelos Moleculares , N-Metilaspartato/farmacologia , Norbornanos/farmacologia , Receptores de Glicina/antagonistas & inibidores , Convulsões/induzido quimicamenteRESUMO
A limited series of bridgehead alkyl-, dialkyl-, and trialkyl-substituted amantadines was synthesized and tested for potential anti-Parkinson activity as dopamine (DA) agonists. The compounds were evaluated using a battery of three murine bioassays, including stimulation of locomotor activity, induction of circling in animals with unilateral striatal lesions, and reversal of reserpine/alpha-methyltyrosine induced akinesia. Apparent mechanistic differences were seen between the methyl-substituted series and the ethyl-substituted series. While activities in both series increase with increasing liphophilicity, the methyl series (1b--d), as well as amantadine itself (1a), exhibit only indirect DA agonist activity, as evidenced by ipsilateral rotation in the circling model and no significant difference from control in reversal of akinesia. The ethyl series (1e,f) exhibits weak but reproducible direct DA agonist activity, as shown by contralateral rotation in the circling assay for 1e and reversal of akinesia by 1e and 1f. The 3-n-propyl derivative (1g) was devoid of any DA agonist activity.
Assuntos
Amantadina/análogos & derivados , Antiparkinsonianos/farmacologia , Amantadina/síntese química , Amantadina/farmacologia , Animais , Antiparkinsonianos/síntese química , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Because of the described immunosuppressive potency of 1-aminoadamantan, the authors prepared conjugates of N-substituted 1-aminoadamantan derivatives with human serum albumin (HSA) and bovine gamma globulin (BGG). To achieve covalent binding of 1-aminoadamantan (1) to HSA and BGG (following the isothiocyanate procedure), 1 was converted to the N-(p-isothiocyanatobenzoyl) derivative of 1-aminoadamantan (4) via the nitro compound (2) and the amino compound (3). The reaction of 4 with HSA and BGG yielded conjugates with thiourea structure. The imidic acid ester hydrochloride (7) and the thioimidic acid ester hydrochloride (11) were prepared from the N-(p-cyanobenzoyl) derivative of 1-aminoadamantan (6) and reacted with HSA and BGG to give conjugates with amidine structure.