Jasplakinolide is a potential candidate for further preclinical development and a lead structure for a novel class of therapeutic agents that can disrupt the actin cytoskeleton in mammalian cells.
In an effort to determine the pharmaceutical utility and the structural requirements for activity against various tumor cell lines, several 6E-hydroximino-4-ene steroids with different side chains and degrees of unsaturation on ring A were synthesized in our laboratory. Evaluation of the synthesized compounds for cytotoxicity against P-388, A-549, HT-29, and MEL-28 tumor cells revealed that some important structural features are required for activity. The presence of a cholesterol-type side chain, which appears to play a major role in determining the biological activity, the existence of a ketone functionality at C-3, and an elevated degree of oxidation on ring A all result in higher bioactivity than other structural motifs.
Enzymes, such as protein kinase C (PKC), are ubiquitously expressed by eukaryotes2 and are an attractive target to guide discovery of new bioactive substances.26 The PKC signaling path constitutes a pivotal mechanism in the regulation of fundamental processes such as protein synthesis, gene expression, and cell proliferation. Consequently, the development of selective, nontoxic PKC inhibitors may provide treatments for cancer3 a'b or viruses.36 Only a few natural product PKC inhibitors have been discovered, and some of the most important are alkaloids such as the staurosporines,4 a~°c helerythrine,44 and balanol.46 We
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