RESUMO
OBJECTIVES: Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. METHODS: Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of ß-carotene bleaching, at 1-200 µm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 µm) assays. KEY FNDINGS: Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of ß-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. CONCLUSIONS: Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/farmacologia , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Antioxidantes/química , Compostos de Bifenilo/química , Células Cultivadas , Ácidos Cumáricos/química , Eletroquímica , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ferricianetos/química , Radicais Livres/química , Humanos , Hidrocarbonetos Fluorados/química , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Oxirredução , Picratos/química , beta Caroteno/químicaRESUMO
This article describes structure-activity relationship (SAR/QSAR) studies on the cytotoxic activity in a human lung adenocarcinoma cell line (A549) of 43 cucurbitacin derivatives. Modeling was performed using the methods partial least squares with discriminant analysis (PLS-DA) and PLS. For both studies, the variables were selected using the ordered predictor selection (OPS) algorithm. The SAR study demonstrated that the presence or absence of cytotoxic activity of the cucurbitacins could be described using information derived from their chemical structures. The QSAR study displayed suitable internal and external predictivity, and the selected descriptors indicated that the observed activity might be related to electrophilic attack on cellular structures or genetic material. This study provides improves the understanding of the cytotoxic activity of cucurbitacins and could be used to propose new cytotoxic agents.
Assuntos
Antineoplásicos/química , Cucurbitacinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cucurbitacinas/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Análise Multivariada , Relação Quantitativa Estrutura-AtividadeRESUMO
19-Hydroxy-6-azapregnanes were obtained from pregnenolone via a 7-azido-5-oxo-6-nor-5,7-secopregnane intermediate. The 6-azapregnane core was built in good yield in a straightforward way from the secosteroid, by means of a Staudinger (aza-Wittig) reaction. Finally the 19-hydroxy-6-azapregnane was transformed into 19-hydroxy-6-azaprogesterone (that cyclized spontaneously to the 19â3 hemiketal) and 6-azaprogesterone. The 6-azapregnanes lacked agonistic/antagonistic activity on the progesterone receptor.
Assuntos
Pregnanos/síntese química , Progesterona/análogos & derivados , Animais , Células COS , Chlorocebus aethiops , Ciclização , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Luciferases/biossíntese , Luciferases/genética , Pregnanos/farmacologia , Progesterona/síntese química , Progesterona/farmacologia , Regiões Promotoras Genéticas , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidoresRESUMO
In the present study, the in vitro cytotoxic effects of six semi-synthetic derivatives of elatol (1) and isoobtusol (2) were investigated. Chemical modifications were performed on the hydroxyl groups aiming to get derivatives of different polarity, namely the hemisuccinate, carbamate and sulfamate. The structural elucidation of the new derivatives was based on detailed NMR and MS spectroscopic analyses. The in vitro cytotoxicity of compounds 1 to 8 was evaluated against A459 and RD tumor cell lines with CC50 values ranging from 4.93 to 41.53 µM. These results suggest that the structural modifications performed on both compounds could be considered a good strategy to obtain more active derivatives.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos de Espiro/química , Linhagem Celular , Humanos , Laurencia/química , Laurencia/metabolismo , Estrutura MolecularRESUMO
Chemical investigation of the roots of Wilbrandia ebracteata Cogn. (Cucurbitaceae) led to the isolation of two new (1- 2) and four known (3- 6) cucurbitacins. Their structures were elucidated by NMR and MS and compared with related compounds. The in vitro cytotoxicity of isolated compounds was evaluated against RD, KB, HCT-8, and A549 cell lines showing strong activity.
Assuntos
Cucurbitaceae/química , Cucurbitacinas/farmacologia , Extratos Vegetais/química , Brasil , Linhagem Celular Tumoral , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Cucurbitacinas/química , Cucurbitacinas/isolamento & purificação , Humanos , Medicina Tradicional , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.
Assuntos
Pregnanolona/análogos & derivados , Pregnanolona/farmacologia , Receptores de GABA-A/metabolismo , Animais , Membrana Celular/metabolismo , Cerebelo/metabolismo , Masculino , Modelos Moleculares , Pregnanolona/síntese química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Conformationally restrained substituted pregnane-20-one derivatives were obtained by an intramolecular nitrene addition onto a C-5/C-6 double bond involving a tethered C-19 sulfamoyl moiety. The resulting aziridine underwent regioselective nucleophilic ring opening at C-5 at room temperature with cyanide, fluoride, and acetate. In the isolated case of acetate, a reversal of regioselectivity was observed at higher temperatures, a result attributed to a rearrangement process involving aziridine ring opening at the C-5 position and subsequent migration of the acetyl moiety to C-6.