期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 7, 页码 2285-2293出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.02.058
关键词
Phenazines; Phenazine 5,10-dioxides; Acute myeloid leukemia; Hypoxia selectivity
资金
- NOVO Exploratory Pre Seed Grant [4462]
- University of Oslo Innovation Fund
- Norwegian Cancer Society
- Western Norway Regional Health Authorities
- School of Pharmacy, University of Oslo
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. (C) 2017 Elsevier Ltd. All rights reserved.
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