Structure-activity relationships of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III.
Structure-activity relationships of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III.
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衍生自 14β-羟基-10-脱乙酰浆果赤霉素 III 的新紫杉烷的结构-活性关系。
DOI：
10.1021/jm00036a004
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发表时间：
1994
影响因子：
7.3
通讯作者：
Bernacki,RJ
中科院分区：
文献类型：
--
作者：
Ojima,I;Park,YH;Sun,CM;Fenoglio,I;Appendino,G;Pera,P;Bernacki,RJ
紫杉醇（紫杉醇）是一种从西部紫杉树皮中分离出来的复杂二萜，目前被认为是癌症化疗中最令人兴奋的先导。1-3泰索帝（多西他赛），一种半合成类似物，也显示出巨大的前景。4紫杉醇和多西他赛对多种肿瘤具有较高的细胞毒活性和较强的抗肿瘤活性，而现有的抗肿瘤药物对这些肿瘤的治疗效果不佳。5 '6 Paclitazone于1992年底被FDA批准用于治疗晚期卵巢癌，目前正在进行乳腺癌和肺癌的II期和III期临床试验。2 Docetamine目前正在美国、欧洲和日本进行II期和III期临床试验。6然而，最近关于紫杉醇和多西他赛临床试验的报告披露，这些高效药物具有许多不希望的副作用以及多药耐药性（MDR）。因此，非常重要的是开发新的抗癌药物，其具有较少的不良副作用、更好的药理学性质和/或针对与这两种药物不同的各种肿瘤类型的活性谱。最近从云南红豆杉（Taxus wallichiana Zucc）的针叶中分离得到一个新的紫杉烷类二萜化合物14/3-羟基-10-去乙酰基浆果赤霉素III（14/3-OH-DAB）。和其他植物部分。8由于在C-14位有一个额外的羟基，14/3-OH-DAB已被证明具有比通常的10-脱乙酰基浆果赤霉素III（DAB）高得多的水溶性，后者目前用于实际生产上述紫杉醇和多西他赛。因此，14/3-OH-DAB衍生的新的抗肿瘤紫杉烷类化合物有望具有显著改善的水溶性、生物利用度和疏水性相关的耐药性。7这些改善的药理学性质很可能与针对不同癌症类型的不良毒性和活性谱的改变有关。新紫杉烷的合成以14/3-OH-DAB为起始原料，在β-内酰胺合成子法的基础上，采用一种高效、实用的偶联方法合成了一系列新的紫杉烷类化合物。9-11因此，具有极高对映体纯度的C-13侧链前体（3R，4S）-1-酰基-3-（EEO）-4-苯基氮杂环丁烷-2-酮1（EE=乙氧基乙基）通过我们有效的手性酯烯醇化物-亚胺环化缩合方法10 '11以78-80%的总产率分四步获得。7，10-DiTroc-14/3-OH-DAB（3）（Troc= 2，2，2-三氯乙氧羰基）是通过与4当量的州立大学（纽约，斯托尼布鲁克）反应制备的。1都灵大学。
Taxol (paclitaxel), a complex diterpene isolated from the bark of the western yew (Taxusbrevifolia), is currently considered the most exciting lead in cancer chemotherapy. 1-3 Taxotere (docetaxel), a semisynthetic analog, also has shown great promise. 4 Paclitaxel and docetaxel possess high cytotoxicity and strong antitumoractivity against different cancers which have not been effectively treated by existing antitumor drugs. 5’6 Paclitaxel was approved by FDA in late 1992 for the treatment of advanced ovarian cancer and is currently in phase II and III clinical trials for breast cancer and lung cancers. 2 Docetaxel is currently in phase II and III clinical trials in United States, Europe, and Japan. 6 A recent report on clinical trials of paclitaxel and docetaxel, however, has disclosed that these highly effective drugs have a number of undesired side effects as well as multidrug resistance (MDR). 1’5’7 Therefore, it is very important to develop new anticancer drugs which have less undesirable side effects, better pharmacological properties, and/or activity spectra against various tumor types different from those of these two drugs. Recently, a novel taxane diterpenoid, 14/3-hydroxy-10-deacetylbaccatin III (14/3-OH-DAB), was isolated from the needles of Taxus wallichiana Zucc. and other plant parts. 8 Because of an extra hydroxyl group at the C-14 position, 14/3-OH-DAB has proven to possess much higher water solubility thanthe usual 10-deacetylbaccatin III (DAB), which is currently used for the practical production of paclitaxel and docetaxel as mentioned above. Therefore, the new antitumor taxanes derivedfrom 14/3-OH-DAB can be expected to have substantially improved water solubility, bioavailability, and hydrophobicity-related drug resistance. 7 These improved pharmacological properties may well be related to the modification of undesirable toxicity and activity spectra against different cancer types. Syntheses of New Taxoids. A series of new taxoids were synthesized from 14/3-OH-DAB using a highly efficient and practical coupling protocol based on the/3-lactam synthon method developed in our laboratory. 9-11 Thus, the C-13 side chain precursors,(3R, 4S)-l-acyl-3-(EEO)-4-phenylazetidin-2-ones 1 (EE= ethoxyethyl) with extremely high enantiomeric purity, were obtained through our efficient chiral ester enolate-imine cyclocondensation method10’11 in four steps in 78-80% overall yields. The 7, 10-DiTroc-14/3-OH-DAB (3)(Troc= 2, 2, 2-trichloroethoxycarbonyl) were prepared by reacting with 4 equiv t State University of New York at Stony Brook. 1 UnivesitA di Torino.