Design, synthesis, and evaluation of indeno[2,1-c]pyrazolones for use as inhibitors against hypoxia-inducible factor (HIF)-1 transcriptional activity
Design, synthesis, and evaluation of indeno[2,1-c]pyrazolones for use as inhibitors against hypoxia-inducible factor (HIF)-1 transcriptional activity
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DOI：
10.1016/j.bmc.2019.115207
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Nakamura, Hiroyuki
中科院分区：
文献类型：
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作者：
Fuse, Shinichiro;Suzuki, Kensuke;Nakamura, Hiroyuki
HIF-1被认为是癌症化疗药物的一个有前途的靶点，为开发能够抑制HIF-1转录活性的合成候选药物创造容易获得的模板是一个重要的追求。在这项研究中，吲哚并[2，1-c]吡唑酮类化合物被设计为易于获得的HIF-1转录活性的合成抑制剂。以市售原料为原料，经4-5步反应合成了9个化合物。在抑制缺氧诱导的HIF-1转录活性的能力评估中，化合物3c的水平高于已知的抑制剂Yc-1。化合物3c抑制HIF-1α蛋白积聚，但不影响HIF-1αmRNA水平。
HIF-1 is regarded as a promising target for the drugs used in cancer chemotherapy, and creating readily accessible templates for the development of synthetic drug candidates that could inhibit HIF-1 transcriptional activity is an important pursuit. In this study, indeno[2,1-c]pyrazolones were designed as readily available synthetic inhibitors of HIF-1 transcriptional activity. Nine compounds were synthesized in 4-5 steps from commercially available starting materials. In evaluations of the ability to inhibit the hypoxia-induced transcriptional activity of HIF-1, compound 3c showed a higher level compared with that of known inhibitor, YC-1. The compound 3c suppressed HIF-1 alpha protein accumulation without affecting the levels of HIF-1 alpha mRNA.