title: Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
authors.forename: Elvar Örn
authors.initials: EÖ
authors.lastname: Viktorsson
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033, Blindern, 0315 Oslo, Norway.
authors.forename: Bendik
authors.initials: B
authors.lastname: Melling Grøthe
authors.affiliation: Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, N-5009 Bergen, Norway.
authors.forename: Reidun
authors.initials: R
authors.lastname: Aesoy
authors.affiliation: Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, N-5009 Bergen, Norway.
authors.forename: Misbah
authors.initials: M
authors.lastname: Sabir
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033, Blindern, 0315 Oslo, Norway.
authors.forename: Simen
authors.initials: S
authors.lastname: Snellingen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
authors.forename: Anthony
authors.initials: A
authors.lastname: Prandina
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway.
authors.forename: Ove Alexander
authors.initials: OA
authors.lastname: Høgmoen Åstrand
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033, Blindern, 0315 Oslo, Norway.
authors.forename: Tore
authors.initials: T
authors.lastname: Bonge-Hansen
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway.
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
authors.affiliation: Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 87, N-5009 Bergen, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Herfindal
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N0316 Oslo, Norway. Electronic address: pal.rongved@farmasi.uio.no.
authors.forename: Pål
authors.initials: P
authors.lastname: Rongved
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D010619:Phenazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D010619:Phenazines; C005247:myxin; C008134:iodinin
keywords: Acute myeloid leukemia; Hypoxia selectivity; Phenazine 5,10-dioxides; Phenazines