Synthesis and Cytotoxic Evaluation of N-Alkyl-2-halophenazin-1-ones

Haruki Kohatsu; Shogo Kamo; Masateru Furuta; Shusuke Tomoshige; Kouji Kuramochi

doi:10.1021/acsomega.0c04253

Synthesis and Cytotoxic Evaluation of N-Alkyl-2-halophenazin-1-ones

ACS Omega. 2020 Oct 16;5(42):27667-27674. doi: 10.1021/acsomega.0c04253. eCollection 2020 Oct 27.

Authors

Haruki Kohatsu¹, Shogo Kamo¹, Masateru Furuta¹, Shusuke Tomoshige¹, Kouji Kuramochi¹

Affiliation

¹ Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yaamazaki, Noda, Chiba 278-8510, Japan.

Abstract

In this study, the synthesis of N-alkyl-2-halophenazin-1-ones has been established. Six N-alkyl-2-halophenazin-1-ones, including WS-9659 B and marinocyanins A and B, were synthesized by the direct oxidative condensation of 4-halo-1,2,3-benzenetriol with the corresponding N-alkylbenzene-1,2-diamines. One of the most significant features of the present method is that it can be successfully applied to the synthesis of N-alkyl-2-chlorophenazin-1-ones. The traditional chlorination of N-alkyl-phenazin-1-ones with N-chlorosuccinimide selectively occurs at the 4-position to afford the undesired N-alkyl-4-chlorophenazin-1-ones. Our synthetic route successfully circumvents this problem, culminating in the first chemical synthesis of WS-9659 B. The cytotoxicity of six N-alkyl-2-halophenazin-1-ones and three N-alkylphenazin-1-ones against human promyelocytic leukemia HL-60, human lung cancer A549, and normal MRC-5 cells was evaluated. Among the compounds tested in this study, 2-chloropyocyanin possesses significant selectivity toward A549 cells. The cytotoxic evaluation provides structural insights into the potency and selectivity of these compounds for cancer cells.