Reidun Aesoy, Ingeborg Nerbø Reiten, Pål Rongved, Lars Herfindal and Elvar Örn Viktorsson
Introduction:
Myxin and iodinin are well known phenazine antibiotics of natural origin. Myxin is a potent and broad-spectrum antimicrobial agent. Iodinin, a close derivative of myxin was recently discovered to be a selective apoptotic inducer of leukemic cell death with high potency. The presented work will cover the synthesis and biological evaluations of new phenazine 5,10-dioxides derived from iodinin and myxin, aimed to target acute myeloid leukemia (AML).
Methodology:
Iodinin, myxin and multiple close structural derivatives were synthesized from commercially available reagents. Structure-activity relationship (SAR) studies were conducted by assessing cytotoxicity of multiple iodinin/myxin analogs against both leukemic and non-malignant cell lines. A cell proliferation reagent (WST-1) was used to assess viability.
Results:
More than one hundred analogs of iodinin and myxin have been synthesized and biologically assessed using the WST-1 cell proliferation assay on three different cell lines (MOLM-13, NRK and H9c2). Carbamate analogs of phenazine 5,10-dioxides proved to be most efficient, demonstrating high potency and selectivity towards the AML cells.
Conclusions:
The presented work demonstrates our efforts made to develop new antileukemic agents derived from the phenazine natural products iodinin and myxin. Multiple structural analogs and prodrugs have been synthesized and screened for anticancer activities. Moreover, their cellular toxicity on healthy cell lines was established as part of conventional SAR-studies. New carbamate prodrugs of iodinin and myxin have been demonstrated to be highly potent and selective towards human AML cells.
