Sawa E, Takahashi M, Kamishohara M, Tazunoki T, Kimura K, Arai M, Miyazaki T, Kataoka S, Nishitoba T
Pharmaceutical Research Laboratory, Kirin Brewery Company, Ltd., 3 Miyahara-cho, Takasaki, Gumma 370-1295, Japan.
J Med Chem. 1999 Aug 26;42(17):3289-99. doi: 10.1021/jm980617f.
We report the structural requirements of the C-terminal tripeptide derivative of Fas (Ac-Ser-Leu-Val-OH, 1) for the inhibitory activity of Fas/FAP-1 binding. The presence of a carboxyl group and a L-Val residue at the C-terminus is essential for the inhibitory activity, and the hydroxyl group of Ser plays an important role as the donor of a hydrogen bond. The introduction of hydrophobic groups to the N-terminal region of 1, especially the phenylaminocarbonyl group (41), showed a remarkable increase in potency. Further improvement was observed by the attachment of the Glu residue to the meta-position of the phenyl ring of 41 (51). The ester derivative of 41 (56) had the ability to induce apoptosis which was dependent on the concentration of anti-Fas antibody in the colon cancer cell line, DLD-1, which expresses both Fas and FAP-1 and is resistant to Fas-induced apoptosis. We are now investigating whether FAP-1 is a main target of 56 and whether the inhibition of Fas/FAP-1 binding by 56 retrieves the apoptotic signal.
我们报道了Fas的C端三肽衍生物（Ac-Ser-Leu-Val-OH，1）对Fas/FAP-1结合抑制活性的结构要求。C端存在羧基和L-缬氨酸残基对抑制活性至关重要，Ser的羟基作为氢键供体发挥重要作用。在1的N端区域引入疏水基团，尤其是苯氨基羰基（41），显示出活性显著增加。通过将Glu残基连接到41苯环的间位（51）观察到进一步改善。41的酯衍生物（56）具有诱导凋亡的能力，这在表达Fas和FAP-1且对Fas诱导凋亡具有抗性的结肠癌细胞系DLD-1中取决于抗Fas抗体的浓度。我们目前正在研究FAP-1是否是56的主要靶点，以及56对Fas/FAP-1结合的抑制是否能恢复凋亡信号。
