Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.
Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.
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DOI：
10.1158/1535-7163.1365.3.11
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发表时间：
2004-11
影响因子：
5.7
通讯作者：
S. Kasibhatla;H. Gourdeau;K. Meerovitch;J. Drewe;Sanjeeva P. Reddy;L. Qiu;Hong Zhang;F. Bergeron
中科院分区：
文献类型：
--
作者：
S. Kasibhatla;H. Gourdeau;K. Meerovitch;J. Drewe;Sanjeeva P. Reddy;L. Qiu;Hong Zhang;F. Bergeron
通过我们基于细胞的凋亡筛选试验，鉴定了一系列新的2-氨基-4-（3-溴-4，5-二甲氧基-苯基）-3-氰基-4H-色烯作为凋亡诱导剂。合成并进一步表征了该系列的几种类似物MX-58151、MX-58276、MX-76747、MX-116214、MX-126303和MX-116407。MX-116407是该系列的先导化合物，在T47 D乳腺癌细胞中诱导细胞凋亡，EC 50为50 nmol/L，抑制细胞生长，GI 50为37 nmol/L。用这些类似物处理细胞导致G2-M期阻滞，裂解基本的促凋亡半胱天冬酶底物，并诱导核碎裂。我们确定这些化合物作为微管蛋白去稳定剂，其结合位点在秋水仙碱结合位点处或附近。该系列化合物在耐药性癌细胞系中也有活性，其中一种类似物（MX-58151）在紫杉醇耐药性、多药耐药性MES-SA/DX 5肿瘤细胞中的GI 50值为2.5 nmol/L。这一系列化合物显示出对增殖细胞与静息细胞的高选择性。有趣的是，这些化合物显示出在体外破坏预先形成的内皮细胞毛细管，并影响功能性脉管系统以在体内诱导肿瘤坏死，因此可能用作肿瘤脉管系统靶向剂。在这些化合物中，MX-116407在远低于细胞毒性剂量的浓度下显示出体外毛细管破坏活性。在一项单独的研究中，我们进一步表征了这一系列化合物的抗肿瘤功效和药代动力学特征，并将MX-116407鉴定为具有作为肿瘤血管靶向剂的明显活性的强效肿瘤诱导剂。
A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent.