Assuntos
Astrócitos/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Morte Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fatores de TempoRESUMO
The total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolols (1, 5, and 6) are described. The two key steps involved are (1) a thermal electrocyclic reaction of the 3-alkenylindole-2-aldoxime 10 and (2) a thermal cyclization of 3-alkynylindole-2-aldoxime 11 to construct the beta-carboline N-oxides 8, which upon heating with acetic anhydride and sequential treatment with trifluoromethanesulfonic anhydride gave the triflates 18. The Stille coupling reaction of 18 with vinylstannane, followed by cleavage of MOM ether, afforded the 1-ethenyl-3-hydroxymethyl-beta-carboline (7a). Subsequent acetylation of 7a yielded the acetate 7b, which was subjected to the Sharpless asymmetric 1,2-dihydroxylation by AD-mix-beta to produce (R)-(-)-pyridindolol K2 (6). Selective acetylation of 6 was effected by Ac(2)O and collidine to form (R)-(-)-pyridindolol K1 (5). By contrast, hydrolysis of 6 provided (R)-(-)-pyridindolol (1).
Assuntos
Carbolinas/síntese química , Indicadores e Reagentes , EstereoisomerismoRESUMO
We are developing the synthesis of biologically interesting condensed-heteroaromatic compounds, including natural products by the thermal electrocyclic reaction of 6 pi electron system incorporating the double bond of the principal aromatic or heteroaromatic ring. In this report, we describe three types of electrocyclic reactions as follows; 1) the synthesis of highly-substituted carbazole alkaloids based on the allene-mediated electrocyclic reaction involving an indole 2,3-bond, 2) the synthesis of beta-carboline alkaloids and isoquinoline-5,8-quinone alkaloids based on the thermal electrocyclic reaction of an 1-azahexatriene system involving an indole 2,3-bond or benzene 1,2-bond, and 3) the synthesis of new tetracyclic pyrido[2,3-b]indole, grossularines, based on the thermal electrocyclic of an 2-azahexatriene system including the indole 2,3-bond.
Assuntos
Produtos Biológicos/síntese química , Carbazóis/síntese química , Carbolinas/síntese química , Química Orgânica , Elétrons , Temperatura Alta , Fenômenos de Química OrgânicaRESUMO
The formal total synthesis of murrayaquinone A (1) and the total synthesis of furostifoline (5) were completed by the construction of 4-oxygenated 3-methylcarbazoles 7 based on a new type of electrocyclic reaction through 2-alkenyl-3-allenylindole intermediates 8 derived from the 2-alkenyl-3-propargylindoles 9, starting from 2-chloroindole-3-carbaldehyde (11). The N,O-bisbenzyloxymethyl group of 16c and 22 underwent a Birch reduction followed by treatment with Triton B to produce the known 4-hydroxy-3-methylcarbazole (7a) and 4-hydroxy-3-methylfuro[3,2-a]carbazole (7b) as precursors of murrayaquinone A (1) and furostifoline (5), respectively. The trifluoromethanesulfonyloxy-3-methylfuro[3,2-alcarbazole (24), prepared from 7b, was subjected to reductive cleavage to provide furostifoline (5).
Assuntos
Alcaloides/síntese química , Benzoquinonas/síntese química , Carbazóis/química , Carbazóis/síntese química , Furanos/síntese química , Eletroquímica , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A new type of beta-carboline nucleus, N-methoxymethyl-4-methyl-beta-carboline (4) was synthesized by thermal electrocyclic reaction of a 1-azahexatriene system, involving the indole 2,3-bond. The key compound N-methoxymethyl-1-methoxycarbonyl-4-methyl-beta-carboline (2) was then prepared in a four-step sequence. The total synthesis of oxopropaline G (1e) was achieved from this key compound in four steps. Furthermore, the enantioselective total syntheses of (+)-oxopropaline D (1c) and its enantiomer were also achieved by application of the Sharpless oxidation-procedure in nine steps from 2.
Assuntos
Antibacterianos/síntese química , Carbolinas/síntese química , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
An enzyme responsible for the ketone-reduction of 4-benzoylpyridine (4BP) was purified 350-fold to homogeneity from the cytosolic fraction of rabbit heart. The purified enzyme exhibited a molecular mass of 110 kDa on gel filtration, and 27 kDa on SDS-PAGE, indicating that it is a tetrameric protein composed of four identical-size subunits. Aromatic aldehydes, ketones, and menadione were effective substrates for the enzyme. Flavonoids were potent inhibitors of the enzyme, but barbiturates or pyrazole was not. Based on this substrate specificity and inhibitor sensitivity, the enzyme was taken to be a carbonyl reductase. Kinetic studies led us to conclude that the reduction of 4BP by the enzyme follows an ordered Bi Bi mechanism. The enzyme also appeared to catalyze the redox (oxidation-reduction) cycling of menadione to produce the superoxide radical. Furthermore, we provide evidence that a hydrophobic pocket, which corresponds to a straight-chain alkyl group of five carbon atoms in length, is located in the substrate-binding site of the enzyme.
Assuntos
Oxirredutases do Álcool/isolamento & purificação , Oxirredutases do Álcool/metabolismo , Miocárdio/enzimologia , Oxirredutases do Álcool/antagonistas & inibidores , Aldeído Redutase , Aldo-Ceto Redutases , Animais , Catálise , Citosol/enzimologia , Inibidores Enzimáticos/farmacologia , Cinética , Masculino , Peso Molecular , Piridinas/química , Piridinas/metabolismo , Quercetina/farmacologia , Coelhos , Especificidade por Substrato , Superóxidos/química , Superóxidos/metabolismoRESUMO
Medroxyprogesterone acetate (MPA) is widely used in endocrine therapy for breast cancer and other diseases. Recently, it has been demonstrated that 9alpha-fluoromedroxyprogesterone acetate (FMPA) also has anti-tumour activity in chemical-induced rat mammary tumour and its activity is greater than that of MPA. In the present study, the physico-chemical properties of FMPA and MPA and their pharmacokinetics in female rats were investigated. Partition coefficients (log P) of FMPA and MPA were 3.1 and 3.8, respectively, while the solubilities of FMPA and MPA in phosphate buffer saline were 3.8 and 1.1 microg/mL, respectively. When the two agents were intravenously or orally administered into female rats, there was no significant difference between their plasma concentrations. However, unmetabolized drug excreted into urine accounted for 4.7 and 0.7% of the intravenous dose of FMPA and MPA, respectively. The free fraction of FMPA in rat plasma was approximately four times that of MPA. Assuming the well-stirred model, hepatic intrinsic clearances of FMPA and MPA were estimated to be 64 and 293 L/h per kg, respectively. In addition, the free fraction of FMPA in blood is estimated to be higher than that of MPA, which may explain the higher anti-tumour activity.
Assuntos
Antineoplásicos/farmacocinética , Medroxiprogesterona/farmacocinética , Congêneres da Progesterona/farmacocinética , Progesterona/análogos & derivados , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Feminino , Humanos , Injeções Intravenosas , Medroxiprogesterona/administração & dosagem , Medroxiprogesterona/sangue , Taxa de Depuração Metabólica , Progesterona/administração & dosagem , Progesterona/sangue , Progesterona/farmacocinética , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Ligação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
A new anti-angiogenic agent, 17 alpha-acetoxy-9 alpha-fluoro-6 alpha-methylprogesterone (9 alpha-fluoromedoroxyprogesterone acetate [FMPA, 9] was synthetized in a 10-step sequence. FMPA (9) had about two orders of magnitude stronger anti-angiogenic activity than medroxyprogesterone acetate (MPA), as estimated in a bioassay involving chorioallantoic membranes of growing chick embryos.
Assuntos
Antineoplásicos/síntese química , Neovascularização Fisiológica/efeitos dos fármacos , Progesterona/análogos & derivados , Animais , Antineoplásicos/farmacologia , Embrião de Galinha , Acetato de Medroxiprogesterona/farmacologia , Progesterona/síntese química , Progesterona/farmacologiaRESUMO
Twenty dibenzoylmethanes with methyl, methoxy, bromo, chloro, or fluoro substitution on either one or both benzene rings were synthesized and assayed for inhibition of the mutagenicity of 2-nitrofluorene in S. typhimurium TA98. 2,2-Dimethoxy, 3,3-dimethoxy and 3,3,4,4-tetramethoxydibenzoylmethane was as active as dibenzoylmethane. None of the halogen-substituted dibenzoylmethanes were active. These results demonstrate that dibenzoylmethanes can inhibit the mutagenicity of 2-nitrofluorene, and that modifications made on the benzene rings of dibenzoylmethane cannot enhance the antimutagenicity of this parent compound.
Assuntos
Antimutagênicos/síntese química , Benzoatos/síntese química , Chalconas , Salmonella typhimurium/efeitos dos fármacos , Antimutagênicos/farmacologia , Benzoatos/farmacologia , Testes de Mutagenicidade , Relação Estrutura-AtividadeRESUMO
dl-Griseofulvin (1a) was prepared by two synthetic pathways. New 6'-congeners (3 and 4) of griseofulvin were also prepared. Their antifungal activities were evaluated and compounds 3 and 4 were found to be less active than 1a. Molecular calculations on 1a, dl-epigriseofulvin (1b), 3 and 4 were undertaken.