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1.
Phytochemistry ; 67(12): 1243-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16777158

RESUMO

Three clerodane diterpenoids, premnones A-C (1-3), were isolated from a chloroform-soluble fraction of Premna tomentosa along with four known flavonoids and three known triterpenoids. Among these isolates, premnones A-C exhibited cytotoxic activity when evaluated against a small panel of tumor cell lines. However, premnone A was found to be inactive when evaluated in a follow-up in vivo hollow fiber assay at the highest dose tested (50mg/kg), using LNCaP, Lu1, and MCF-7 cells.


Assuntos
Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Neoplasias/tratamento farmacológico , Folhas de Planta/química , Verbenaceae/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos Clerodânicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indonésia , Espectroscopia de Ressonância Magnética , Masculino
2.
J Nat Prod ; 69(3): 414-7, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16562848

RESUMO

Fractionation by pH zone-refining countercurrent chromatography of an extract of the stem bark of Erythroxylum pervillei, obtained on a kilogram scale in southern Madagascar, led to the isolation and characterization of four tropane aromatic ester alkaloids as minor constituents, namely, pervilleines G (5) and H (6) and cis-pervilleines B (7) and F (8). Their structures were determined by spectroscopic data interpretation.


Assuntos
Erythroxylaceae/química , Plantas Medicinais/química , Tropanos/química , Tropanos/isolamento & purificação , Humanos , Madagáscar , Estrutura Molecular , Casca de Planta/química , Estereoisomerismo
3.
Phytother Res ; 20(1): 62-5, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16397845

RESUMO

Cytotoxicity-guided fractionation of the stems of Helicteres hirsuta, of Indonesian origin, led to the isolation and identification of six lignans, namely, (+/-)-pinoresinol, (+/-)-medioresinol, (+/-)-syringaresinol, (-)-boehmenan, (-)-boehmenan H and (+/-)-trans-dihydrodiconiferyl alcohol. Of these isolates, (+/-)-pinoresinol exhibited potent cytotoxic effects when evaluated against a small panel of cancer cell lines.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Lignanas/isolamento & purificação , Lignanas/toxicidade , Malvaceae/química , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Indonésia , Lignanas/química , Espectrometria de Massas/métodos , Estrutura Molecular , Caules de Planta/química , Testes de Toxicidade
4.
J Mass Spectrom ; 40(3): 389-99, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15674857

RESUMO

Maytansine, a potent clinically evaluated plant-derived anti-tumor drug, and its microbial counterpart, ansamitocin P-3, showed a substantially higher cytoxicity than many other anti-tumor drugs. Owing to a shortage of material and lack of sufficiently sensitive analytical methods at the time, no metabolism studies were apparently carried out in conjunction with the initial preclinical and clinical studies on maytansine, but some products of decomposition during the period of storage of the formulated drug were reported. In the current study, the in vitro metabolism of maytansine and ansamitocin P-3 was studied after incubation with rat and human liver microsomes in the presence of NADPH, and with rat and human plasma and whole blood, using liquid chromatography/multi-stage mass spectrometry. Unchanged ansamitocin P-3 and 11 metabolites and unchanged maytansine and seven metabolites were profiled and the structures of some metabolites were tentatively assigned based on their multi-stage electrospray ion-trap mass fragmentation data and in some cases accurate mass measurement. The major pathway of ansamitocin P-3 metabolism in human liver microsomes appears to be demethylation at C-10. Oxidation and sequential oxidation/demethylation also occurred, although to a lesser extent. However, the major pathway of maytansine metabolism in human liver microsomes is N-demethylation of the methylamide of the ester moiety. Several minor pathways including O/N-demethylation, oxidation and hydrolysis of the ester bond were also observed. There were no differences in maytansine metabolism between rat and human liver microsomes; however, the rate of metabolism of ansamitocin P-3 was different in rat and human liver microsomes. About 20% of ansamitocin P-3 was converted to its metabolites in rat liver microsomes and about 70% in human liver microsomes under the same conditions. Additionally, 10-O-demethylated ansamitocin P-3 was also detected in the urine after i.v. bolus administration of ansamitocin P-3 to Sprague-Dawley male rats. No metabolites were detected following incubation of maytansine and ansamitocin P-3 with human and rat whole blood and plasma.


Assuntos
Antineoplásicos/metabolismo , Maitansina/análogos & derivados , Maitansina/metabolismo , Animais , Cromatografia Líquida , Humanos , Masculino , Maitansina/sangue , Maitansina/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray
5.
J Pharm Biomed Anal ; 36(4): 815-21, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15533675

RESUMO

Ansamitocin P-3 (AP3) is a potent maytansinoid antitumor agent isolated from microorganisms and mosses. In this study, a highly sensitive and specific electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for quantitation of AP3 was developed and validated. AP3 was extracted from rat plasma along with the internal standard, depsipeptide FK228 (NSC-630176, FR) with ethyl acetate. Components in the extract were separated on a 50mm x 2.1mm Betabasic C 85 microm stainless steel column by isocratic elution with 70% acetonitrile/0.9% formic acid. The liquid flow was passed through a pre-source splitter and 5% of the eluent was introduced into the API source. The components were analyzed in the multiple-reaction-monitoring (MRM) mode as the precursor/product ion pair of m/z 635.2/547.2 for AP3 and of m/z 541.5/424.0 for the internal standard FR. Linear calibration curves were obtained in the range 1-500 ng/mL using 0.2 mL rat plasma. The within-day coefficients of variation (CVs) were 12.9, 6.7, and 5.5% and the between-day CVs were 10.4, 6.5, and 6.4% (all n = 5) at 1, 10, and 200 ng/mL, respectively. A formulation based on normal saline and PEG300 was then developed and Sprague-Dawley male rats were given this formulated drug by i.v. bolus. Plasma drug concentrations were measured by this method and the pharmacokinetics were analyzed by standard techniques. Plasma concentration-time profiles were found to follow a triexponential decline and the terminal phase was nearly flat, suggesting that the drug distributed in deep tissue compartments or organs and then equilibrates slowly with the blood stream.


Assuntos
Maitansina/análogos & derivados , Maitansina/análise , Maitansina/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Cromatografia Líquida/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Espectrometria de Massas/métodos , Ratos , Ratos Sprague-Dawley
6.
Chem Pharm Bull (Tokyo) ; 52(1): 1-26, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14709862

RESUMO

Maytansine and its congeners have been isolated from higher plants, mosses and from an Actinomycete, Actinosynnema pretiosum. Many of these compounds are antitumor agents of extraordinary potency, yet phase II clinical trials with maytansine proved disappointing. The chemistry and biology of maytansinoids has been reviewed repeatedly in the late 1970s and early 1980s; the present review covers new developments in this field during the last two decades. These include the use of maytansinoids as "warheads" in tumor-specific antibodies, preliminary metabolism studies, investigations of their biosynthesis at the biochemical and genetic level, and ecological issues related to the occurrence of such typical microbial metabolites in higher plants.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/toxicidade , Bactérias/metabolismo , Biotransformação , Briófitas/química , Ensaios Clínicos como Assunto , Humanos , Maitansina/química , Maitansina/toxicidade , Plantas Medicinais/química , Plantas Medicinais/genética , Engenharia de Proteínas , Relação Estrutura-Atividade
7.
Biochim Biophys Acta ; 1589(2): 140-50, 2002 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-12007789

RESUMO

Palmitoylation of cysteines 3 and 5 is necessary for targeting Lck to lipid rafts and is needed for Lck function in T cell receptor (TCR) signaling. Point mutations of cysteines 3 and 5 result in a form of Lck that fails to associate with the plasma membrane, which limits the usefulness of this genetic approach to address the role of palmitoylation in the distribution of Lck within the plasma membrane. To circumvent this problem, we sought to identify a palmitic acid analogue that would enable plasma membrane association of Lck, but not facilitate its localization within lipid rafts. Here we examined the effects of the heteroatom-substituted analogue of palmitic acid, 13-oxypalmitic acid (13-OP), on Lck subcellular localization and function. 13-OP is similar in chain length to palmitic acid, but possesses reduced hydrophobicity. We found that treatment of cells with 13-OP inhibited incorporation of omega-[(125)I]iodopalmitate into Lck. 13-OP inhibited localization of Lck to lipid rafts without altering its membrane localization. Consistent with the dissociation of Lck from rafts, treatment with 13-OP abolished Lck association with the GPI-anchored protein, CD48, but not the transmembrane glycoprotein CD4. Jurkat T cells treated with 13-OP showed marked reduction in tyrosine phosphorylation and activation of mitogen-activated protein kinase upon TCR stimulation. In conclusion, the less hydrophobic analogue of palmitate, 13-OP, alters the normal acylation of Lck that provides Lck with the necessary hydrophobicity and tight packing order required for inclusion in lipid rafts.


Assuntos
Membrana Celular/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Ácidos Palmíticos/farmacologia , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Antígenos CD/química , Antígenos CD4/química , Antígeno CD48 , Proteínas de Fluorescência Verde , Humanos , Interações Hidrofóbicas e Hidrofílicas , Radioisótopos do Iodo , Células Jurkat/efeitos dos fármacos , Proteínas Luminescentes , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Microscopia de Fluorescência , Ácidos Palmíticos/química , Receptores de Antígenos de Linfócitos T/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transfecção
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