Ojima I, Chakravarty S, Inoue T, Lin S, He L, Horwitz S B, Kuduk S D, Danishefsky S J
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4256-61. doi: 10.1073/pnas.96.8.4256.
Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel-i.e., the stabilization of microtubules leading to mitotic arrest-is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [3H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.
紫杉醇（paclitaxel）是从太平洋紫杉（短叶红豆杉，Taxus brevifolia）中提取的一种复杂二萜类化合物，堪称癌症化疗领域最重要的新药。紫杉醇的细胞毒性作用机制，即微管稳定导致有丝分裂停滞，如今另外四种最近鉴定出的天然产物——刺参醇、埃坡霉素A和B以及盘状软骨素——也具备。它们竞争性抑制[3H]紫杉醇与微管结合的能力强烈表明存在一个共同的结合位点。最近，我们开发出了紫杉醇的非芳香族类似物，这些类似物保持了高细胞毒性和与微管蛋白的结合能力（例如，诺他赛）。我们现在提出一个共同药效基团，它将紫杉醇、诺他赛、埃坡霉素、刺参醇和盘状软骨素统一起来，并对与这些化合物相关的大量构效关系数据作出合理解释。从共同药效基团中获得的见解促使开发出了一种具有已证实的细胞毒性和微管蛋白结合活性的杂合构建体。
