Actin‐Binding Marine Macrolides: Total Synthesis and Biological Importance

Abstract

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.

Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity

“…Small molecule marine natural products that target actin filaments with high affinity and potently interfere with actin filament dynamics have been shown to display cytotoxicity against several forms of multidrug resistant tumors (2)(3)(4)(5)(6)(7). For this reason, their candidacy as clinical chemotherapeutic treatments has gained significant attention (8).…”

Developmental Biology of Neoplastic Growth

“…A number of macrolides share essentially the same aliphatic side chain, the presumed major determinant of their binding (reviewed in Yeung and Paterson 2002). In fact, aplyronine A without the side chain lost its activity, whereas the side chain retained the activity (Kigoshi et al 2002).…”

Synthesis of antimicrofilament marine macrolides: Synthesis and configurational assignment of a C 5 –C 16 degradation fragment of reidispongiolide A

“…1), isolated from the blue-green algae Scytonema pseudohofmanni (4), aplyronines (e.g., 2), isolated from the sea hare Aplysia kurodai (5), and sphinxolides (e.g., 3, planar structure), first reported from an unidentified Pacific nudibranch (6) and later reisolated from the New Caledonian marine sponges Neosiphonia superstes and Reidispongia coreulea, along with the congeneric reidispongiolides (e.g., 4, planar structure) (7,8). A related family of trisoxazole-containing marine macrolides, typified by mycalolide A (5) and jaspisamide A (6), are also antimicrofilament agents (9). Recently, an x-ray crystal structure of the latter compound bound to actin (10) highlighted the importance of the characteristic N-vinyl formamide-containing side chain, common to all these macrolides, in determining their biological activity.…”

“…Recently, an x-ray crystal structure of the latter compound bound to actin (10) highlighted the importance of the characteristic N-vinyl formamide-containing side chain, common to all these macrolides, in determining their biological activity. Moreover, all these actin-binding macrolides inhibit the proliferation of human cancer cell lines; for example, the scytophycins and sphinxolides exhibit potent cytotoxicity against L1210 and KB cells, with IC 50 values ranging from ng͞ml to pg͞ml (9). In addition, aplyronine A shows potent antitumor activity in vivo and has potential as a clinical candidate (9).…”

“…Moreover, all these actin-binding macrolides inhibit the proliferation of human cancer cell lines; for example, the scytophycins and sphinxolides exhibit potent cytotoxicity against L1210 and KB cells, with IC 50 values ranging from ng͞ml to pg͞ml (9). In addition, aplyronine A shows potent antitumor activity in vivo and has potential as a clinical candidate (9). Notably, both the scytophycins and sphinxolides circumvent multidrug resistance mediated by the overexpression of P-glycoprotein or multidrug resistance protein (11).…”