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New prodrugs and analogs of the phenazine 5,10-dioxide natural products iodinin and myxin promote selective cytotoxicity towards human acute myeloid leukemia cells

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dc.contributor.author Viktorsson, Elvar Örn
dc.contributor.author Aesoy, Reidun
dc.contributor.author Støa, Sindre
dc.contributor.author Lekve, Viola
dc.contributor.author Døskeland, Stein Ove
dc.contributor.author Herfindal, Lars
dc.contributor.author Rongved, Pål
dc.date.accessioned 2022-06-22T01:01:11Z
dc.date.available 2022-06-22T01:01:11Z
dc.date.issued 2021-05
dc.identifier.citation Viktorsson , E Ö , Aesoy , R , Støa , S , Lekve , V , Døskeland , S O , Herfindal , L & Rongved , P 2021 , ' New prodrugs and analogs of the phenazine 5,10-dioxide natural products iodinin and myxin promote selective cytotoxicity towards human acute myeloid leukemia cells ' , RSC Medicinal Chemistry , vol. 12 , no. 5 , pp. 767-778 . https://doi.org/10.1039/d1md00020a
dc.identifier.issn 2632-8682
dc.identifier.other PURE: 30060946
dc.identifier.other PURE UUID: 5f137621-5c69-4a80-8e1b-a4897a38dc20
dc.identifier.other Scopus: 85107014471
dc.identifier.uri https://hdl.handle.net/20.500.11815/3257
dc.description Funding Information: We thank the University of Oslo, School of Pharmacy, The Research Council of Norway, The Norwegian Cancer Society and Novo Pre Seed for funding this research. We also acknowledge professor Frode Rise and senior engineer Dirk Petersen for their maintenance of excellent NMR-facility at the University of Oslo. We would like to express gratitude as well to Dr. Alexander H. Åstrand for proofreading the experimental part of this work. Publisher Copyright: © The Royal Society of Chemistry.
dc.description.abstract Novel chemotherapeutic strategies for acute myeloid leukemia (AML) treatment are called for. We have recently demonstrated that the phenazine 5,10-dioxide natural products iodinin ( 3) and myxin ( 4) exhibit potent and hypoxia-selective cell death on MOLM-13 human AML cells, and that the N-oxide functionalities are pivotal for the cytotoxic activity. Very few structure-activity relationship studies dedicated to phenazine 5,10-dioxides exist on mammalian cell lines and the present work describes our efforts regarding in vitro lead optimizations of the natural compounds iodinin ( 3) and myxin ( 4). Prodrug strategies reveal carbamate side chains to be the optimal phenol-attached group. Derivatives with no oxygen-based substituent (-OH or -OCH 3) in the 6th position of the phenazine skeleton upheld potency if alkyl or carbamate side chains were attached to the phenol in position 1. 7,8-Dihalogenated- and 7,8-dimethylated analogs of 1-hydroxyphenazine 5,10-dioxide ( 21) displayed increased cytotoxic potency in MOLM-13 cells compared to all the other compounds studied. On the other hand, dihalogenated compounds displayed high toxicity towards the cardiomyoblast H9c2 cell line, while MOLM-13 selectivity of the 7,8-dimethylated analogs were less affected. Further, a parallel artificial membrane permeability assay (PAMPA) demonstrated the majority of the synthesized compounds to penetrate cell membranes efficiently, which corresponded to their cytotoxic potency. This work enhances the understanding of the structural characteristics essential for the activity of phenazine 5,10-dioxides, rendering them promising chemotherapeutic agents.
dc.format.extent 12
dc.format.extent 767-778
dc.language.iso en
dc.relation.ispartofseries RSC Medicinal Chemistry; 12(5)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Bráðahvítblæði
dc.subject Lyf
dc.subject Acute myeloid leukemia
dc.subject Chemotherapeutic agents
dc.subject Biochemistry
dc.subject Molecular Medicine
dc.subject Pharmacology
dc.subject Pharmaceutical Science
dc.subject Drug Discovery
dc.subject Organic Chemistry
dc.title New prodrugs and analogs of the phenazine 5,10-dioxide natural products iodinin and myxin promote selective cytotoxicity towards human acute myeloid leukemia cells
dc.type /dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article
dc.description.version Peer reviewed
dc.identifier.pmid 34124675
dc.identifier.doi https://doi.org/10.1039/d1md00020a
dc.relation.url http://www.scopus.com/inward/record.url?scp=85107014471&partnerID=8YFLogxK
dc.contributor.department Faculty of Pharmaceutical Sciences


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