peloruside-a and Neoplasms

Marine sponges are an excellent source of bioactive secondary metabolites with potential therapeutic value in the treatment of diseases. One group of compounds of particular interest is the microtubule-stabilizing agents, the most well-known compound of this group being paclitaxel (Taxol), an anti-cancer compound isolated from the bark and leaves of the Pacific yew tree. This review focuses on two of the more recent additions to this important class of drugs, peloruside A and zampanolide, both isolated from marine sponges. Peloruside A was isolated from Mycale hentscheli collected in New Zealand coastal waters, and it already shows promising anti-cancer activity. Two other potent bioactive compounds with different modes of action but isolated from the same sponge, mycalamide A and pateamine, will also be discussed. The fourth compound, zampanolide, most recently isolated from the Tongan sponge Cacospongia mycofijiensis, has only recently been added to the microtubule-stabilizing group of compounds, and further work is in progress to determine its activity profile relative to peloruside A and other drugs of this class.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Epoxy Compounds; Humans; Lactones; Macrolides; Microtubules; Neoplasms; Porifera; Pyrans; Thiazoles

Drugs that affect microtubule dynamics, including the taxanes and vinca alkaloids, have been a mainstay in the treatment of leukemias and solid tumors for decades. New, more effective microtubule-targeting agents continue to enter into clinical trials and some, including the epothilone ixapebilone, have been approved for use. In contrast, several other drugs of this class with promising preclinical data were later shown to be ineffective or intolerable in animal models or clinical trials. In this review, we discuss the molecular mechanisms as well as preclinical and clinical results for a variety of microtubule-targeting agents in various stages of development. We also offer a frank discussion of which microtubule-targeting agents are amenable to further development based on their availability, efficacy and toxic profile.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged Bicyclo Compounds, Heterocyclic; Cell Division; Clinical Trials as Topic; Colchicine; Drug Delivery Systems; Drug Screening Assays, Antitumor; Epothilones; Humans; Lactones; Macrolides; Microtubules; Neoplasms; Steroids; Taxoids; Tubulin Modulators; Vinca Alkaloids

The microtubule-stabilizing agent (+)-peloruside A has emerged as a potential therapeutic agent for the treatment of cancer. Two total syntheses have been published and these reports have stimulated additional studies to advance the methodology and strategies for accessing this molecular architecture. This review details the biological data, modeling and conformation analyses, and synthetic studies toward the synthesis of (+)-peloruside A, that were reported prior to December 2007.

Topics: Animals; Antibiotics, Antineoplastic; Bridged Bicyclo Compounds, Heterocyclic; Humans; Indicators and Reagents; Lactones; Models, Molecular; Neoplasms; Structure-Activity Relationship