RESUMO
This paper reports some of the advantages and limitations of solid-supported liquid-liquid extraction (SLE) for the rapid purification of organic compound libraries. Issues of solvent compatibility, compound compatibility, and technical methods are addressed. In addition the prospective use of calculated log P values is investigated to determine which impurities will be effectively removed by this technique. In addition SLE is shown to be complementary and in some cases superior to solid-phase extraction (SPE) methods for library purification. This is especially true when the desired products have functionality equivalent to that of the impurity to be removed.
RESUMO
The successful synthesis of dolastatin 11, a depsipeptide originally isolated from the mollusk Dolabella auricularia, permitted us to study its effects on cells. The compound arrested cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network. In a dose-and time-dependent manner, F-actin was rearranged into aggregates, and subsequently the cells displayed dramatic cytoplasmic retraction. The effects of dolastatin 11 were most similar to those of the sponge-derived depsipeptide jasplakinolide, but dolastatin 11 was about 3-fold more cytotoxic than jasplakinolide in the cells studied. Like jasplakinolide, dolastatin 11 induced the hyperassembly of purified actin into filaments of apparently normal morphology. Dolastatin 11 was qualitatively more active than jasplakinolide and, in a quantitative assay we developed, dolastatin 11 was twice as active as jasplakinolide and 4-fold more active than phalloidin. However, in contrast to jasplakinolide and phalloidin, dolastatin 11 did not inhibit the binding of a fluorescent phalloidin derivative to actin polymer nor was it able to displace the phalloidin derivative from polymer. Thus, despite its structural similarity to other agents that induce actin assembly (all are peptides or depsipeptides), dolastatin 11 may interact with actin polymers at a distinct drug binding site.
Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Actinas/efeitos dos fármacos , Antineoplásicos/farmacologia , Proteínas de Bactérias , Depsipeptídeos , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Actinas/imunologia , Actinas/metabolismo , Actinas/ultraestrutura , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Dipodomys , Corantes Fluorescentes/metabolismo , Isotiocianatos/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Faloidina/farmacologiaRESUMO
A phytochemical investigation of the chloroform leaf extract of Alchornea latifolia has been undertaken. Along with the triterpenoids taraxerone, friedelin, epifriedelinol, and taraxerol, the plant also contains seco-3,4-friedelin (dihydroputranjivic acid) (1) and seco-3,4-taraxerone (2). These A-ring-opened triterpenoids show in vitro cytotoxic activity against Hep-G2 and A-431 human cancer cell lines and are potent inhibitors of topoisomerase II.
