吩嗪-5,10-二氧化物天然产物碘菌素、粘菌素及其衍生物的全合成与抗白血病活性评价
Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives.
作者信息
Viktorsson Elvar Örn, Melling Grøthe Bendik, Aesoy Reidun, Sabir Misbah, Snellingen Simen, Prandina Anthony, Høgmoen Åstrand Ove Alexander, Bonge-Hansen Tore, Døskeland Stein Ove, Herfindal Lars, Rongved Pål
机构信息
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, 0315 Oslo, Norway.
出版信息
Bioorg Med Chem. 2017 Apr 1;25(7):2285-2293. doi: 10.1016/j.bmc.2017.02.058. Epub 2017 Feb 28.
A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.
通过几步反应实现了吩嗪-5,10-二氧化物天然产物碘菌素和黏液菌素以及由它们衍生的新化合物的高效全合成，关键步骤是1,6-二羟基吩嗪的双-N-氧化。由碘菌素制备的类似物，包括黏液菌素和2-乙氧基-2-氧代乙氧基衍生物，在常压和低氧水平下对人癌细胞（MOLM-13白血病细胞）完全保留了细胞毒性作用。此外，碘菌素首次显示出对缺氧具有选择性。白血病细胞死亡诱导的构效关系表明，N-氧化物官能团的水平对细胞毒性至关重要。还表明，活性仅需要两个酚羟基中的一个，从而允许另一个酚羟基在不损失效力的情况下进行修饰。
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