Chemistry and Biology of Kahalalides

Abstract

With drug discovery from marine natural products hailing a renaissance over the past 5 years, the use of marine extracts in the search for biologically active natural products continues to be a powerful approach for the identification of lead compounds for chemistry programs involved in drug discovery.1 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 tyrosine kinase ErbB3 (HER3) and the phosphatidylinositol 3-kinase-Akt signaling pathways in sensitive cell lines, which suggests that KF (6) and isoKF (22) are involved in an unknown oncosis signaling pathway, though the mechanism of action has not yet been completely characterized.103-107 The kahalalides would represent the first anticancer drugs that can inhibit HER3 receptors.