Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side Chain

Kentaro Futaki; Momoko Takahashi; Kenta Tanabe; Akari Fujieda; Hideo Kigoshi; Masaki Kita

doi:10.1021/acsomega.9b01099

Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side Chain

ACS Omega. 2019 May 16;4(5):8598-8613. doi: 10.1021/acsomega.9b01099. eCollection 2019 May 31.

Authors

Kentaro Futaki¹, Momoko Takahashi¹, Kenta Tanabe¹, Akari Fujieda², Hideo Kigoshi¹, Masaki Kita^{1

2}

Affiliations

¹ Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
² Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.

Abstract

Aplyronine A (ApA) is an antitumor marine macrolide that induces an protein-protein interaction (PPI) between actin and tubulin. The C1-C9 macrolactone part including the C7 N,N,O-trimethylserine (TMSer) ester is important for its highly potent activities. To develop new antitumor PPI inducers, four aplyronine analogues were synthesized, which bear the C1-C9 macrolactone part with 0-2 TMSer ester(s) and the C24-C34 actin-binding side chain. Despite exhibiting potent actin-depolymerizing activity comparable to that of ApA, these analogues did not show potent cytotoxicity or depolymerize microtubules. Molecular modeling studies suggested that the whole macrolactone moiety of aplyronines was important to fix the conformation of the C7 TMSer ester moiety, while the linear C1-C9 part was insufficient. Still, our study newly proposed that fixed conformations of the C7 or C9 TMSer esters in aplyronines that protrude from the actin surface are important for binding to tubulin and inhibit microtubule dynamics.