TX-2152: A conformationally rigid and electron-rich diyne analogue of FTY720 with in vivo antiangiogenic activity
TX-2152: A conformationally rigid and electron-rich diyne analogue of FTY720 with in vivo antiangiogenic activity
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DOI：
10.1016/j.bmc.2008.07.003
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发表时间：
2008-08-15
影响因子：
3.5
通讯作者：
Hori, Hitoshi
中科院分区：
文献类型：
--
作者：
Nakayama, Shinichi;Uto, Yoshihiro;Hori, Hitoshi
我们设计了具有构象刚性和富电子炔链的FTY 720类似物作为抗血管生成剂（单炔1：TX-2148，二炔2：TX-2152，三炔3：TX-2256）。分子轨道（MO）计算结果表明，与FTY 720相比，最低未占据MO和最高占据MO的位置由苯环向炔链逐渐增加.这些炔属类似物是从对羟基苯基乙醇作为起始原料合成的。炔链的构建通过使用Sonogashira交叉偶联反应和脱甲硅烷基溴化两步的迭代策略进行。单炔1、二炔2和三炔3的相应总产率为27%（11步）、13%（13步）和10%（15步）。通过鸡胚绒毛尿囊膜（CAM）测定评价这些炔属类似物和FTY 720的体内抗血管生成活性，并与已知的抗血管生成剂TNP-470的活性进行比较。在10 μ g/CAM的剂量下，二炔2显示出比FTY 720（77%抑制）和其它炔属类似物（单炔1：42%抑制，三炔3：60%抑制）和TNP-470（82%抑制）更有效的抗血管生成活性（90%抑制），而没有显示出毒性。二炔2在5和2.5 μ g/CAM的剂量下也具有有效的抑制活性。这些结果表明，FTY 720的C8烷基链的柔性不是其抗血管生成活性所必需的。我们认为二炔2（TX-2152）可能是抗肿瘤药物发现中抗血管生成剂的一个有希望的候选药物。(C)2008爱思唯尔有限公司保留所有权利。
We designed FTY720 analogues with conformationally rigid and electron-rich acetylenic chains as anti-angiogenic agents ( the monoyne 1: TX-2148, the diyne 2: TX-2152, the triyne 3: TX-2256). Molecular orbital ( MO) calculations of our designed acetylenic analogues and FTY720 showed that the localization of the lowest unoccupied MO and the highest occupied MO increased from phenyl ring to acetylenic chain compared with that of FTY720. These acetylenic analogues were synthesized from p-hydroxyphenylethanol as a starting material. The construction of the acetylenic chain was carried out by an iterative strategy using a Sonogashira cross-coupling reaction and desilylative bromination in two steps. The corresponding overall yields of the monoyne 1, the diyne 2, and the triyne 3 were 27% ( 11 steps), 13% ( 13 steps), and 10% ( 15 steps). The in vivo antiangiogenic activities of these acetylenic analogues and FTY720 were evaluated by the chick embryo chorioallantoic membrane ( CAM) assay and compared to the activities of the known antiangiogenic agent TNP-470. The diyne 2 showed more potent antiangiogenic activity ( 90% inhibition) than FTY720 ( 77% inhibition) and other acetylenic analogues ( the monoyne 1: 42% inhibition, the triyne 3: 60% inhibition), and TNP-470 ( 82% inhibition) at a dose of 10 mu g/CAM, without showing toxicity. The diyne 2 also had potent inhibitory activity at a dose of 5 and 2.5 mu g/CAM. These results indicate that the flexibility of C8 alkyl chain of FTY720 is not required for its antiangiogenic activity. We suggest that the diyne 2 ( TX-2152) may be a promising candidate as an antiangiogenic agent for antineoplastic drug discovery. (C) 2008 Elsevier Ltd. All rights reserved.