Chemistry and biology of kahalalides.
Chemistry and biology of kahalalides.
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DOI：
10.1021/cr100187n
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发表时间：
2011-05-11
期刊：
影响因子：
62.1
通讯作者：
Hamann MT
中科院分区：
文献类型：
--
作者：
Gao J;Hamann MT
天然产物继续作为开发候选药物的有价值的起点，而开发治疗剂的第一步是鉴定与特定靶点或感兴趣的受体结合的先导化合物。2然后通过合成或半合成一些类似物来研究先导化合物的构效关系（sar），以确定最大活性的关键识别元素。3然而，到20世纪90年代中期，就主要制药公司的参与而言，天然产物在药物发现中的作用变得不那么重要了。4这种下降的原因包括人们认识到天然产物的缺点，包括获取和供应方面的困难，天然产物的复杂性导致的结构阐明和合成，以及对与已发表结构和国际收藏相关的知识产权的担忧。此外，通过组合化学方法制备的大量化合物的可用性为随机筛选和合理设计的起始材料提供了廉价的大量分子。尽管如此，由于分析化学、光谱高通量筛选的新发展以及组合化学产生的令人失望的线索数量，天然产物化学领域在过去5年中迎来了复兴。1,7 -9目前，始于20世纪70年代的海洋天然产物的化学和生物学基础科学研究终于为海洋衍生药物的发现取得了成果。Ziconotide （Prialt； Elan制药公司）是一种最初从热带锥螺中发现的肽，是2004年12月美国批准用于治疗疼痛的第一种海洋衍生化合物。然后，在2007年10月，trabectedin （Yondelis; PharmaMar）获得批准，成为欧盟第一个海洋抗癌药物。工业和学术科学家之间的合作继续应对发现、理解和开发新的抗癌药物所涉及的挑战。10其他几种来自海洋的候选化合物也在研发中，并正在美国和欧洲进行I-III期临床试验，用于治疗各种癌症。11-13本文综述了kahalalides，这是一种从草食性海洋软体动物Elysia rufescens、Elysia ornata或Elysia tifolia及其藻类食物Bryopsis pennata中分离出来的结构无关的抑郁肽家族。该家族中最具活性的两种化合物，卡哈拉利特F (KF)(6)和isoKF(22)，已经在肝细胞癌、非小细胞肺癌（NSCLC）和黑色素瘤的II期临床试验中进行了评估。此外，KF(6)正在重度牛皮癣患者的II期临床试验中进行评估。最重要的是KF(6)能有效抑制受体
Natural products continue to serve as valuable starting points in developing druglike candidates, and the first step in the development of therapeutic agents is the identification of lead compounds that bind to a specific target or receptor of interest. 2 Structure-activity relationships (SARs) of lead compounds are then studied by synthesis or semisynthesis of a number of analogues to define the key recognition elements for maximal activity. 3 However, the role of natural products in drug discovery became a lower priority in terms of participation by the major pharmaceutical companies by the mid-1990s. 4 Reasons for this decline include the perceived disadvantages of natural products, including difficulties in access and supply, structure elucidation and synthesis because of the complexity of natural products, and concerns about intellectual property rights associated with published structures and international collections. In addition, the availability of large collections of compounds prepared by combinatorial chemistry methods provides inexpensive access to large numbers of molecules for random screening and starting materials for rational design. 5, 6 Nevertheless, the natural products chemistry field has welcomed a renaissance over the past 5 years because of new developments in analytical chemistry, spectroscopy highthroughput screening, and a disappointing number of leads generated through combinatorial chemistry. 1, 7-9 Currently, basic scientific research in chemistry and biology of marine natural products that started in the 1970s has finally borne fruit for marine-derived drug discovery. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered from a tropical cone snail, was the first marine-derived compound approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) was approved and became the first marine anticancer drug in the European Union. Collaborations between industrial and academic scientists continue to meet the challenges involved in discovering, understanding, and developing new anticancer drugs. 10 Several other candidate compounds from marine origins are in the pipeline and are being evaluated in phase I-III clinical trials for the treatment of various cancers in the United States and in Europe. 11-13 Here, we review the kahalalides, a family of structurally unrelated depsipeptides isolated from the herbivorous marine mollusk Elysia rufescens, Elysia ornata, or Elysia grandifolia and their algal diet of Bryopsis pennata. 14-27 Two of the most active compounds of this family, kahalalide F (KF)(6) and isoKF (22), have been evaluated in phase II clinical trials in hepatocellular carcinoma, non-small-cell lung cancer (NSCLC), and melanoma. Moreover, KF (6) is being evaluated in phase II clinical trials in patients with severe psoriasis. 83-93 Of greatest significance is the fact that KF (6) can effectively inhibit receptor