Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka 569-1094, Japan.
Bioorg Med Chem. 2011 Jun 1;19(11):3372-7. doi: 10.1016/j.bmc.2011.04.036. Epub 2011 Apr 22.
We designed a phenylglycine (Phg)-incorporated ascidiacyclamide (ASC) analogue, cyclo(-Phg-oxazoline-d-Val-thiazole-Ile-oxazoline-d-Val-thiazole- ([Phg]ASC), with the aim of stabilizing the square conformation of ASC through interactions between amino acid side chains. X-ray diffraction analysis showed that [Phg]ASC has a square structure, similar to ASC, in which the sec-butyl group of Ile and the benzene ring of Phg are in close proximity. Consistent with that finding, ¹H NMR experiments revealed significant high-field shifts in the sec-butyl group of Ile, which suggests a potential for CH/π interactions between the sec-butyl group of Ile and the benzene ring of Phg. The CD spectra of [Phg]ASC were less affected by TFE titration or increasing temperature than those of ASC. In addition, [Phg]ASC showed approximately three times greater toxicity toward HL-60 cells than ASC. Thus the potently cytotoxic conformation of [Phg]ASC may be stabilized by CH/π interactions between the side chains of the Ile and Phg residues.
我们设计了一种苯甘氨酸（Phg）掺入的海鞘素（ASC）类似物，环（Phg-噁唑啉-d-Val-噻唑-Ile-噁唑啉-d-Val-噻唑-（[Phg]ASC），旨在通过氨基酸侧链之间的相互作用稳定 ASC 的方形构象。X 射线衍射分析表明，[Phg]ASC 具有类似于 ASC 的方形结构，其中 Ile 的仲丁基和 Phg 的苯环非常接近。与这一发现一致，¹H NMR 实验表明 Ile 的仲丁基发生了显著的高场位移，这表明 Ile 的仲丁基和 Phg 的苯环之间可能存在 CH/π 相互作用。与 ASC 相比，[Phg]ASC 的 CD 光谱受 TFE 滴定或升高温度的影响较小。此外，[Phg]ASC 对 HL-60 细胞的毒性比 ASC 大约强三倍。因此，[Phg]ASC 的强效细胞毒性构象可能通过 Ile 和 Phg 残基的侧链之间的 CH/π 相互作用得到稳定。
