Actin-binding marine macrolides: total synthesis and biological importance.
Marine organisms produce a fascinating range of structurally diverse secondary metabolites, which often possess unusual and sometimes unexpected biological activities. This structural diversity makes these marine natural products excellent molecular probes for the investigation of biochemical pathways. Recently, a number of novel and stereochemically complex macrolides, having a large macrolactone (22- to 44-membered) ring, that interact with the actin cycloskeleton have been isolated from different marine sources. Actin, like tubulin, is a major component of the cytoskeleton and has important cellular functions. Although the details of these interactions are still under investigation, these marine macrolides are becoming increasingly important as novel molecular probes to help elucidate the cellular functions of actin. Owing to their potent antitumor activities, these compounds, for example the aplyronines, also have potential for preclinical development in cancer chemotherapy. Their appealing molecular structures, with an abundance of stereochemistry, and biological significance, coupled with the extremely limited availability from the marine sources, have stimulated enormous interest in the synthesis of these compounds. This review summarizes the biological properties of these unusual marine natural products and features the recently completed total syntheses of swinholide A, scytophycin C, aplyronine A, mycalolide A--all of these being potent cytotoxic agents that target actin--and a diastereoisomer of ulapualide A. Rather than detailing each individual step of these multistep total syntheses, the different synthetic strategies, key reactions, and methods adopted for controlling the stereochemistry are compared.
Yeung
Kap-Sun
KS
University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK. kapsun.yeung@bms.com
Paterson
Ian
I
D000199:Actins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism
D000199:Actins; D000970:Antineoplastic Agents; D018942:Macrolides