Opin vísindi

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

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


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
Author: Viktorsson, Elvar Örn
Aesoy, Reidun
Støa, Sindre
Lekve, Viola
Døskeland, Stein Ove
Herfindal, Lars
Rongved, Pål
Date: 2021-05
Language: English
Scope: 12
Department: Faculty of Pharmaceutical Sciences
Series: RSC Medicinal Chemistry; 12(5)
ISSN: 2632-8682
DOI: https://doi.org/10.1039/d1md00020a
Subject: Bráðahvítblæði; Lyf; Acute myeloid leukemia; Chemotherapeutic agents; Biochemistry; Molecular Medicine; Pharmacology; Pharmaceutical Science; Drug Discovery; Organic Chemistry
URI: https://hdl.handle.net/20.500.11815/3257

Show full item record

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

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.

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.

Files in this item

This item appears in the following Collection(s)