Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.
Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.
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DOI：
10.1016/j.bmc.2012.05.068
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Kisliuk, Roy L.
中科院分区：
文献类型：
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作者：
Gangjee, Aleem;Zhao, Ying;Ihnat, Michael A.;Thorpe, Jessica E.;Bailey-Downs, Lora C.;Kisliuk, Roy L.
关键词：
我们设计、合成和评价了13个新的三环吲哚并[2，1-d]嘧啶类化合物作为RTK抑制剂。这些类似物是通过1，2-亚苯二乙腈的狄克曼缩合，然后与碳酸胍的环合反应合成的，得到2-amino-3，9-dihydro-indeno[2，1-d]pyrimidin-4-one.4位磺化，然后用适当取代的苯胺置换，得到目标化合物。与标准相比，这些化合物是血小板衍生生长因子受体β(PDGFRβ)的有效抑制剂，并在鸡胚绒毛尿囊膜(CAM)检测中抑制血管生成。此外，化合物7对9种肿瘤细胞株具有两位数的纳米分子GI50，对临床前NCI 60肿瘤细胞系小组中的29种其他肿瘤细胞株具有亚微摩尔GI50。在B16-F10同基因小鼠黑色素瘤模型中，化合物7也显示出显著的体内抑制肿瘤生长和血管生成的作用。
We designed, synthesized and evaluated thirteen novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor β (PDGFRβ) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI50 against nine tumor cell lines, a submicromolar GI50 against twenty nine of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model.
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影响因子：
7.3
作者：
Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Ihnat, Michael;Shenoy, Satyendra;Kisliuk, Roy L.
通讯作者：
Kisliuk, Roy L.
影响因子：
4.8
作者：
Baldwin, J;Farajallah, AM;Phillips, MA
通讯作者：
Phillips, MA
影响因子：
2.7
作者：
Gangjee, Aleem;Namjoshi, Ojas A.;Ihnat, Michael A.;Buchanan, Aaron
通讯作者：
Buchanan, Aaron
影响因子：
4.3
作者：
Naumov, George N.;Akslen, Lars A.;Folkman, Judah
通讯作者：
Folkman, Judah
影响因子：
8.8
作者：
通讯作者：
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