Nicolaou K C, Trujillo J I, Jandeleit B, Chibale K, Rosenfeld M, Diefenbach B, Cheresh D A, Goodman S L
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Bioorg Med Chem. 1998 Aug;6(8):1185-208. doi: 10.1016/s0968-0896(98)00090-x.
Recent studies demonstrated that peptide and antibody antagonists of integrin alpha v beta 3 block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck's arylether/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (alpha v beta 3, alpha IIb beta 3, and alpha v beta 5) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of alpha IIb beta 3 (IC50 = 14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 micrograms/embryo).
最近的研究表明，整合素αvβ3的肽和抗体拮抗剂可阻断血管生成和肿瘤生长。本文描述了一系列基于硝基芳基醚的非肽模拟物的设计、合成及生物学评价。这些化合物的设计基于默克公司的芳基醚/α-氨基酸/胍骨架，并引入了一种新型硝基芳基体系。对合成的模拟物针对多种整合素（αvβ3、αIIbβ3和αvβ5）进行测试，以确定它们的结合选择性和抑制细胞粘附的能力。还对选定的化合物进行了鸡胚绒毛尿囊膜（CAM）试验，以测试其体内抑制血管生成的能力。从生成的化合物库中，化合物16和19被证明是αIIbβ3的强效和选择性抑制剂（IC50 = 14 nM），而化合物11在体内对血管生成表现出优异的抑制作用（30微克/胚胎）。
