2. Academic Validation
  3. Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives

Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives

  • Bioorg Med Chem. 2017 Apr 1;25(7):2285-2293. doi: 10.1016/j.bmc.2017.02.058.
Elvar Örn Viktorsson 1,  Bendik Melling Grøthe 2,  Reidun Aesoy 3,  Misbah Sabir 3,  Simen Snellingen 2,  Anthony Prandina 1,  Ove Alexander Høgmoen Åstrand 1,  Tore Bonge-Hansen 2,  Stein Ove Døskeland 4,  Lars Herfindal 3,  Pål Rongved 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
  • 2 Department of Chemistry, University of Oslo, PO Box 1033, Blindern, 0315 Oslo, Norway.
  • 3 Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, N-5009 Bergen, Norway.
  • 4 Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway. Electronic address: pal.rongved@farmasi.uio.no.
PMID: 28284865 DOI: 10.1016/j.bmc.2017.02.058
Abstract

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.

Keywords

Acute myeloid leukemia; Hypoxia selectivity; Phenazine 5,10-dioxides; Phenazines.

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