Organic Chemistry Laboratory, University of Bayreuth, Universitätsstraße 30, 95440 Bayreuth (Germany).
ChemMedChem. 2014 Apr;9(4):847-54. doi: 10.1002/cmdc.201300531. Epub 2014 Feb 23.
Two analogues of the discontinued tumor vascular-disrupting agent verubulin (Azixa®, MPC-6827, 1) featuring benzo-1,4-dioxan-6-yl (compound 5 a) and N-methylindol-5-yl (compound 10) residues instead of the para-anisyl group on the 4-(methylamino)-2-methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single-digit nanomolar IC50 values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (Ebind =-9.8 kcal mol(-1) ) than verubulin (Ebind =-8.3 kcal mol(-1) ), 10 suppressed the formation of vessel-like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular-disrupting effects that led to hemorrhages and extensive central necrosis in the tumor.
两种已停产的肿瘤血管破坏剂长春瑞滨类似物（Azixa ® ，MPC-6827，1），其特征是苯并-1,4-二恶烷-6-基（化合物 5a）和 N-甲基吲哚-5-基（化合物 10）残基取代了 4-（甲氨基）-2-甲基喹唑啉药效团上的对茴香基，它们的抗肿瘤功效超过了先导化合物。它们对一组 9 种肿瘤细胞系具有抗增殖作用，IC50 值为个位数纳摩尔，而对非恶性成纤维细胞没有影响。吲哚 10 在包括结肠、乳腺、卵巢和生殖细胞癌细胞系在内的 7 种肿瘤细胞系中超过了长春瑞滨。与表明化合物 10 可能与微管蛋白的秋水仙碱结合位点结合更紧密（Ebind =-9.8 kcal mol（-1））而不是长春瑞滨（Ebind =-8.3 kcal mol（-1））的对接研究一致，10 抑制了内皮细胞中类似管状的管的形成，并在鸡胚的绒毛尿囊膜中以纳摩尔浓度破坏血管。当应用于携带高度血管化 1411HP 生殖细胞瘤异种移植瘤的裸鼠时，化合物 10 显示出明显的血管破坏作用，导致肿瘤出血和广泛的中心坏死。
