Development of Highly Cytotoxic and Actin‐Depolymerizing Biotin Derivatives of Aplyronine A

Abstract

Tied up: a PEG-linked biotin derivative of marine macrolide aplyronine A (ApA) is shown to exhibit potent cytotoxicity and cause actin disassembly in tumor cells. This method of introducing a PEG linker at the end of the aliphatic tail should offer perspectives for developing and using versatile actin-targeting molecular probes. PEG=poly(ethylene glycol).

Total Synthesis of Aplyronine C

“…Recent work has shown that aplyronine A causes caspase-dependent apoptosis with rapid disassembly of the actin cytoskeleton and dephosphorylation of focal adhesion kinase 10 and has suggested an interaction between the aplyronine–actin complex and a secondary biomolecule such as Arp2/3. 11 …”

“…11−16 Moreover, they hold great potential for the development of biomolecular probes and novel actin-targeting therapeutic agents. It is a testament to the severe challenge presented by these complex polyketides that, despite considerable effort from several groups, 12−16 only one prior total synthesis of aplyronines A–C has been achieved, as reported by Yamada and Kigoshi.…”

Bioorganic Studies on the Key Natural Products from Venomous Mammals and Marine Invertebrates

“…Based on the MS/MS analysis of tryptic peptide fragments and immunoblotting analysis, we confirmed that these proteins were actin-related proteins 2/3 (Arp2 and Arp3), respectively. 46 Both Arp2 and Arp3 were also competitively eluted by 5 from the resin as with actin (lane 2). These results suggested the presence of specific interactions between ApA and actin-related proteins.…”

“…45 Here we describe the development and use of the ApA derivatives, that is, investigations of their target proteins and dynamic behavior in tumor cells. 46,47 3.1 Synthesis and Biological Activities of ApA Derivatives. Previous studies of the structureactivity relationship 48 and photoaffinity labeling experiments 49 have established that the C24C34 aliphatic tail part of 5 is important for potent actin-depolymerizing activity.…”

“…53 The hydrophobic cleft between SD1 and SD3 of actin, to which 5 binds, are highly conserved among actin, Arp2, and Arp3. 46 Thus, it was suggested that ApA (5) may bind to Arp2 or Arp3 to give 1:1 complexes, as with the actinaplyronine A complex, and inhibit the ability of the Arp2/3 complex to bind to and branch F-actin. These properties may help to enhance the potent actin filament disassembly caused by 5.…”