Medicinal chemistry on marine alkaloid as a seed of the development for a new anticancer drug in Malaya area

ECteinassidin 743是从海洋囊藻Ecteinassida turbinata中分离得到的天然产物，目前在美国和欧盟的II/III期临床试验中已被证明是一种非常有前途的、非常有效的抗肿瘤药物。作为我们在从泰国海洋动物中分离和鉴定生物活性化合物中寻找新的抗癌代谢物的一部分，我们成功地发现了一株泰国被衣藻，Eteinassida thurstoni Herdman 1891，这是在普吉岛周围生长的第一种含有这类分子的亚洲被衣藻。我们报道了从经KCN处理的泰国被衣酸盐中分离和结构鉴定的衣冠菌素770和786。使用这种方法分离天然海产品具有增加不稳定的胞外杀菌素类化合物的产率的优点。此外，我们发现了一种蓝色海绵Xestospongia sp.，生长在泰国湾的西昌岛周围，通过同样的策略，我们成功地从克级分离出了肾霉素M，它也具有很强的抗肿瘤活性。顺便说一句，最耐人寻味的问题之一是如何保持药物开发所需的胞外毒素的稳定供应：通过从海洋来源分离还是通过全合成。结合该系列天然产物短步合成的开发，我们以前报道了三环内酰胺中间体的制备和ABC环状模型化合物的部分合成。在我们的研究结果的鼓舞下，我们将这些策略应用于制备具有两个苯环上的特征取代基的胞外抗菌素的ABCDE环系统。

Ecteinascidin 743 is a natural product isolated from the marine tunicate Ecteinascida turbinata, which has been demonstrated to be a highly promising, exceeding potent antitumor agent currently in phase II/III clinical trials in USA and EU. As a part of our search for new anticancer metabolites in the isolation and characterization of biologically active compounds from Thai marine animals, we have succeeded to find a Thai tunicate, Ecteinascida thurstoni Herdman 1891, which is the first example of the Asian tunicate containing this class of molecules, growing around Phuket Island. We report the isolation and structural elucidation of ecietnascidins 770 and 786 from the KCN pretreated Thai tunicate. Isolation of natural marine products using this procedure has the advantage of increasing the yield of labile Ecteinascidin-type compounds. Furthermore, we found a blue sponge, Xestospongia sp., growing around Sichang Island in the Gulf of Thailand, and by the same strategy, we are succeeded the gram-scale isolation of renieramycins M, which has also potent amtitumor activity.By the way, one of the most intriguing problems, which is how to maintain a consistent supply of ecteinascidins for drug development : by isolation from marine sources or by total synthesis still remains. In connection with the development of a short-step synthesis of this series of natural product, we have previous reported the preparation of the tricyclic lactam intermediate, and the partial synthesis of the ABC ring model compound. Encourage by the results of our studies, we apply these strategies for preparation of the ABCDE ring system of ecteinascidins, having characteristic substituents in both benzene rings.