TY - JOUR
T1 - Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives
AU - Viktorsson, Elvar Örn
AU - Melling Grøthe, Bendik
AU - Aesoy, Reidun
AU - Sabir, Misbah
AU - Snellingen, Simen
AU - Prandina, Anthony
AU - Høgmoen Åstrand, Ove Alexander
AU - Bonge-Hansen, Tore
AU - Døskeland, Stein Ove
AU - Herfindal, Lars
AU - Rongved, Pål
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Hypoxia selectivity
KW - Phenazine 5,10-dioxides
KW - Phenazines
UR - http://www.scopus.com/inward/record.url?scp=85015720520&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2017.02.058
DO - 10.1016/j.bmc.2017.02.058
M3 - Article
C2 - 28284865
AN - SCOPUS:85015720520
SN - 0968-0896
VL - 25
SP - 2285
EP - 2293
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 7
ER -