ABSTRACT
An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and biologically evaluated. This hybrid induced protein-protein interactions between two major cytoskeletal proteins actin and tubulin in the same manner as aplyronine A, and exhibited potent cytotoxicity and actin-depolymerizing activity. The importance of the methoxy group in the N,N,O-trimethylserine ester was clarified by the structure-activity relationship studies of the amino acid moiety by using the hybrid analogs. Furthermore, the comparison of the actin-depolymerizing activities between the side chain analogs of aplyronine A and swinholide A showed that the side chain analog of swinholide A had much weaker actin-depolymerizing activity than that of aplyronine A.
Subject(s)
Antineoplastic Agents , Macrolides , Actins/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HeLa Cells , Humans , Macrolides/chemistry , Macrolides/pharmacology , Marine Toxins , Structure-Activity RelationshipABSTRACT
An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and evaluated for biological activities. The hybrid retained strong cytotoxicity and actin-depolymerizing activity. In addition, the hybrid induced protein-protein interactions (PPI) between actin and tubulin in the manner of aplyronine A.