Futaki Kentaro, Takahashi Momoko, Tanabe Kenta, Fujieda Akari, Kigoshi Hideo, Kita Masaki
Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan.
Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan.
ACS Omega. 2019 May 16;4(5):8598-8613. doi: 10.1021/acsomega.9b01099. eCollection 2019 May 31.
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 ,,-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.
阿普利罗宁A（ApA）是一种抗肿瘤海洋大环内酯类化合物，可诱导肌动蛋白和微管蛋白之间发生蛋白质-蛋白质相互作用（PPI）。包括C7位三甲基丝氨酸（TMSer）酯在内的C1 - C9大环内酯部分对其高效活性至关重要。为开发新型抗肿瘤PPI诱导剂，合成了四种阿普利罗宁类似物，它们带有含0 - 2个TMSer酯的C1 - C9大环内酯部分以及C24 - C34肌动蛋白结合侧链。尽管这些类似物表现出与ApA相当的强效肌动蛋白解聚活性，但它们并未显示出强效细胞毒性，也不会使微管解聚。分子模拟研究表明，阿普利罗宁的整个大环内酯部分对于固定C7 TMSer酯部分的构象很重要，而线性的C1 - C9部分则不够。不过，我们的研究新提出，阿普利罗宁中从肌动蛋白表面突出的C7或C9 TMSer酯的固定构象对于与微管蛋白结合并抑制微管动力学很重要。
