抄録
Aplyronine A (ApA, 1) is an antitumor macrolide from the sea hare Aplysia kurodai. A PEG-linked biotin derivative 4 of ApA was prepared and was shown to exhibit potent cytotoxicity and cause actin disassembly in tumor cells. With the use of this probe, actin-related proteins 2/3 (Arp2 and Arp3) as well as actin were specifically purified from the whole lysate of HeLa S3 cells. Arp2 and Arp3 are the key proteins of the Arp2/3 complex, which binds to the sides of an existing actin filament and initiates growth of a new actin filament to form branched-actin-filament networks. Thus, ApA (1) may inhibit the ability of the Arp2/3 complex to bind to and branch F-actin, which may enhance actin filament disassembly. To the best of our knowledge, this is the first example that actin-depolymerizing molecules can also bind to actin-related proteins. A fluorescent derivative 7 possessing a tetramethylrhodamine moiety was also prepared from 1. With the use of this probe, time-lapse analyses in the living HEp2 cells that expressed GFP-actin as well as HeLa S3 cells were performed. Further structural and functional analyses of ApA-binding proteins as well as their roles in the antitumor activities of 1 will be presented.
