Hung D T, Nerenberg J B, Schreiber S L
Howard Hughes Medical Institute, Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
Chem Biol. 1994 Sep;1(1):67-71. doi: 10.1016/1074-5521(94)90042-6.
Cell permeable ligands of low molecular weight can be used to dissect complex cellular processes. During the past several years this approach has been particularly important in the study of intracellular signal transduction. Discodermolide, a marine natural product, appears to inhibit a signaling pathway in immune cells. The structure of natural discodermolide is known, but its absolute stereochemistry is not. We set out to make both enantiomers and to investigate their biological activity.
Both enantiomers of discodermolide were prepared by total synthesis. Surprisingly, both enantiomers have biological activity, and their effects seem to be distinct in that they arrest cells at different stages of the cell cycle. A specific binding activity was identified for (+)-discodermolide but not for (-)-discodermolide, and the binding of the two enantiomers was not competitive.
Both enantiomers of discodermolide have antiproliferative activity, but they act by distinct mechanisms and appear to have distinct cellular targets. The natural product is the (+)-enantiomer, which blocks the cell cycle in the G2 or M phase. The (-)-enantiomer blocks cells in S phase. Both may be useful in studies of the regulation of the cell cycle; we have also identified a specific binding activity for (+)-discodermolide, and have provided evidence that it interacts with a functionally relevant receptor.
低分子量的细胞可渗透配体可用于剖析复杂的细胞过程。在过去几年中，这种方法在细胞内信号转导研究中尤为重要。Discodermolide是一种海洋天然产物，似乎能抑制免疫细胞中的一条信号通路。天然Discodermolide的结构已知，但其绝对立体化学未知。我们着手合成其两种对映体并研究它们的生物活性。
通过全合成制备了Discodermolide的两种对映体。令人惊讶的是，两种对映体均具有生物活性，且它们的作用似乎不同，因为它们能使细胞停滞在细胞周期的不同阶段。已鉴定出（+）-Discodermolide具有特异性结合活性，而（-）-Discodermolide没有，且两种对映体的结合不具有竞争性。
Discodermolide的两种对映体均具有抗增殖活性，但它们的作用机制不同，且似乎具有不同的细胞靶点。天然产物是（+）-对映体，它在G2或M期阻断细胞周期。（-）-对映体在S期阻断细胞。两者在细胞周期调控研究中可能都有用；我们还鉴定出了（+）-Discodermolide的特异性结合活性，并提供了证据表明它与功能相关的受体相互作用。
