RESUMO
Four binuclear phosphanesilver(I) dithiocarbamates, {cyclohexyl3PAg(S2CNRR')}2 for Râ¯=â¯R'â¯=â¯Et (1), CH2CH2 (2), CH2CH2OH (3) and Râ¯=â¯Me, R'â¯=â¯CH2CH2OH (4) have been synthesised and characterised by spectroscopy and crystallography, and feature tri-connective, µ2-bridging dithiocarbamate ligands and distorted tetrahedral geometries based on PS3 donor sets. The compounds were evaluated for anti-bacterial activity against a total of 12 clinically important pathogens. Based on minimum inhibitory concentration (MIC) and cell viability tests (human embryonic kidney cells, HEK 293), 1-4 are specifically active against Gram-positive bacteria while demonstrating low toxicity; 3 and 4 are active against methicillin resistant S. aureus (MRSA). Across the series, 4 was most effective and was more active than the standard anti-biotic chloramphenicol. Time kill assays reveal 1-4 to exhibit both time- and concentration-dependent pharmacokinetics against susceptible bacteria. Compound 4 demonstrates rapid (within 2â¯h) bactericidal activity at 1 and 2â¯×â¯MIC to reach a maximum decrease of 5.2â¯log10â¯CFU/mL against S. aureus (MRSA).
Assuntos
Antibacterianos , Complexos de Coordenação , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Prata , Tiocarbamatos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Cloranfenicol/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Avaliação Pré-Clínica de Medicamentos , Prata/química , Prata/farmacologia , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiocarbamatos/farmacologiaRESUMO
Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G(1) cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.
Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/farmacologia , Benzopiranos/farmacologia , Butiratos/farmacologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzopiranos/síntese química , Benzopiranos/química , Butiratos/síntese química , Butiratos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fase G1/genética , Humanos , Isotiocianatos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenilcarbamatos/síntese química , Fenilcarbamatos/química , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , Distribuição Aleatória , Receptores Androgênicos/genética , Transdução de Sinais/genética , Tiocarbamatos/síntese química , Tiocarbamatos/químicaRESUMO
Brassinin hydrolase (BHAb), an inducible enzyme produced by the plant pathogen Alternaria brassicicola under stress conditions, catalyzes the hydrolysis of the methyl dithiocarbamate group of the phytoalexin brassinin, to indolyl-3-methanamine, methane thiol and carbonyl sulfide. Thirty four substrate inspired compounds, bioisosteres of brassinin and a range of related compounds, were evaluated as potential substrates and inhibitors of BHAb for the first time. While six compounds containing thiocarbamate, carbamate and carbonate groups displayed inhibitory activity against BHAb, only two were found to be substrates (thionecarbamate and dithiocarbamate). Methyl naphthalen-1-yl-methyl carbamate, the most potent inhibitor of the six, and methyl N'-(1-methyl-3-indolylmethyl)carbamate inhibited BHAb through a reversible noncompetitive mechanism (K(i)=89±9 and 695±60µM, respectively). Importantly, these carbamate inhibitors were resistant to degradation by A. brassicicola. Carbonates were also inhibitory of BHAb, but a quick degradation by A. brassicicola makes their potential use as crop protectants less likely. Overall, these results indicate that indolyl and naphthalenyl carbamates are excellent lead structures to design new paldoxins that could inhibit the detoxification of brassinin by A. brassicicola.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidrolases/antagonistas & inibidores , Tiocarbamatos/química , Alternaria/enzimologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Hidrolases/metabolismo , Indóis/química , Cinética , Especificidade por Substrato , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologiaRESUMO
Two new boldine derivatives: the 3-thiocarbamateboldine (3) and the 2,9-O,O-diacetyl-3-thiocarbamateboldine (4) have been synthesized and their cytotoxicity evaluated.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Aporfinas/química , Aporfinas/síntese química , Peumus/química , Tiocarbamatos/química , Tiocarbamatos/síntese química , Aporfinas/isolamento & purificação , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Tiocarbamatos/isolamento & purificaçãoRESUMO
The dimethyl-, di-n-butyl-, and diphenyltin(IV) dithiocarbamate (dtc) complexes [{R2Sn(L-dtc)}x] 1-7 (1, L = L1, R = Me; 2, L = L1, R = n-Bu; 3, L = L2, R = Me, x = infinity; 4, L = L2, R = n-Bu; 5, L = L3, R = Me, x = 2; 6, L = L3, R = n-Bu, x = 2; 7, L = L3, R = Ph, x = 2) have been prepared from a series of secondary amino acid (AA) homologues as starting materials: N-benzylglycine (alpha-AA derivative = L1), N-benzyl-3-aminopropionic acid (beta-AA derivative = L2), and N-benzyl-4-aminobutyric acid (gamma-AA derivative = L3). The resulting compounds have been characterized by elemental analysis, mass spectrometry, IR and NMR ((1)H, (13)C, and (119)Sn) spectroscopy, thermogravimetric analysis, and X-ray crystallography, showing that in all complexes both functional groups of the heteroleptic ligands are coordinated to the tin atoms. By X-ray diffraction analysis, it could be shown that [{Me2Sn(L2-dtc)}x] (3) is polymeric in the solid state, while the complexes derived from L3 (5-7) have dinuclear 18-membered macrocyclic structures of the composition [{R2Sn(L3-dtc)}2]. For the remaining compounds, it could not be established with certainty whether the structures are macrocyclic or polymeric. A theoretical investigation at the B3LYP/SBKJC(d,p) level of theory indicated that the alpha-AA-dtc complexes might have trinuclear macrocyclic structures. The macrocyclic complexes 5-7 have a double-calix-shaped conformation with two cavities large enough for the inclusion of aliphatic and aromatic guest molecules. They are self-complementary for the formation of supramolecuar synthons that give rise to 1D molecular arrangements in the solid state. Preliminary recognition experiments with tetrabutylammonium acetate have shown that the [{R2Sn(L3-dtc)}2] macrocycles 6 and 7 might interact simultaneously with anions (AcO(-)), which coordinate to the tin atoms, and organic cations (TBA(+)), which accommodate within the hydrophobic cavity (ion-pair recognition).
Assuntos
Aminoácidos/química , Compostos Macrocíclicos/química , Compostos Orgânicos de Estanho/química , Tiocarbamatos/química , Ânions/química , Cátions/química , Cristalografia por Raios X , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Compostos Macrocíclicos/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos Orgânicos de Estanho/síntese química , Espectrofotometria Infravermelho , Termogravimetria , Tiocarbamatos/síntese químicaRESUMO
Brassinin is a plant defense metabolite with antimicrobial activity produced de novo by a variety of Brassica species in response to stress, that is, a phytoalexin. The inhibition of brassinin oxidase (BO), a brassinin-detoxifying enzyme produced by the phytopathogenic fungus Leptosphaeria maculans, is a target in our continuing search for novel crop protection agents. To probe the substrate specificity of BO, in particular the mechanism of the detoxification step, several analogues of brassinin, including functional group isosteres ((mono/dithio)carbamate, urea, and thiourea) and homologue methyl tryptaminedithiocarbamate, were investigated using fungal cultures and purified BO. It was concluded that the essential structural features of substrates of BO were: (i) an -NH at the (mono/dithio)carbamate, urea or thiourea group; (ii) a methylene bridge between indole and the functional group; (iii) a methyl or ethyl group attached to the thiol moiety of the (mono/di)thiocarbamate group. A general stepwise pathway for the oxidation of brassinin was proposed that accounts for the structural requirements of detoxification of brassinin analogues in L. maculans. All compounds that were BO substrates appeared to be oxidized in mycelial cultures to aldehydes, except for the two most polar compounds N'-(3-indolylmethyl)-N''-methylurea and methyl N'-(3-indolylmethyl)carbamate. The substrate specificity of BO suggests that selective inhibitors can be designed for the potential control of L. maculans.
Assuntos
Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Inativação Metabólica , Indóis/química , Indóis/farmacologia , Extratos Vegetais/metabolismo , Tiocarbamatos/química , Tiocarbamatos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Ascomicetos/metabolismo , Ascomicetos/patogenicidade , Brassicaceae/metabolismo , Brassicaceae/microbiologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Indóis/síntese química , Doenças das Plantas/microbiologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiocarbamatos/síntese químicaRESUMO
A series of aminocarbamic acid derivatives, containing fragments of substituted hydrazine and dithiocarbamic acid, was synthesized. The immunopharmacologic studies showed these that derivatives exerted immunotropic, mainly suppressive effects (PFC, circulating immunoglobulins, E-RFC, A-RFC). Some of these compounds, however, caused significant increase of weight of the popliteal lymph nodes. The immunotropic activity of the newly synthesized preparations is comparable with the action of sodium diethyldithiocarbamate (imuthiol).