Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives

Cheng Hua Huang,Hsien-Shou Kuo,Yuh-Ling Lin,Jia-Wen Liu

doi:10.3390/molecules14072306

Cheng Hua Huang, Hsien-Shou Kuo + Show 2 more

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https://doi.org/10.3390/molecules14072306

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Abstract

Aziridine-containing compounds have been of interest as anticancer agents since late 1970s. The design, synthesis and study of triaziquone (TZQ) analogues with the aim of obtaining compounds with enhanced efficacy and reduced toxicity are an ongoing research effort in our group. A series of bis-type TZQ derivatives has been prepared and their cytotoxic activities were investigated. The cytotoxicity of these bis-type TZQ derivatives were tested on three cancer lines, including breast cancer (BC-M1), oral cancer (OEC-M1), larynx epidermal cancer (Hep2) and one normal skin fibroblast (SF). Most of these synthetic derivatives displayed significant cytotoxic activities against human carcinoma cell lines, but weak activities against SF. Among tested analogues the bis-type TZQ derivative 1a showed lethal effects on larynx epidermal carcinoma cells (Hep2), with an LC50 value of 2.02 mM, and also weak cytotoxic activity against SF cells with an LC50 value over 10 mM for 24 hr treatment. Comparing the viability of normal fibroblast cells treated with compound 1a and TZQ, the LC50 value of the latter was 2.52 mM, indicating more toxicity than compound 1a. This significantly decreased cytotoxicity of compound 1a towards normal SF cells, while still maintaining the anticancer activity towards Hep2 cells is an interesting feature. Among the seven compounds synthesized, compound 1c has similar toxicity effects on the three cancer cell lines and SF normal cells as the TZQ monomer.

Highlights

The bioreductive aziridinylbenzoquinone drugs are a class of compounds designed to exploit one of the features of solid tumor biology, namely tumor hypoxia, caused by an inadequate blood supply to solid tumors; such regions generally are resistant to radiation, chemotherapeutic and other O2-requiring treatments [1,2,3,4]
These agents are composed of aziridinyl moieties on a quinone structure, and they are converted by reductive metabolism into a bifunctional alkylating species that can cross-link major groove DNA by interacting predominantly at guanine-N7 [9]
The aziridinyl moiety within the analogues served an important alkylation group [18], but the cytotoxic effects of the synthetic analogues towards carcinoma cells might not solely be due to the aziridinyl moiety, as the quinone structure is common in numerous natural products that are associated with antitumor activities [20]

Summary

Introduction

The bioreductive aziridinylbenzoquinone drugs are a class of compounds designed to exploit one of the features of solid tumor biology, namely tumor hypoxia, caused by an inadequate blood supply to solid tumors; such regions generally are resistant to radiation, chemotherapeutic and other O2-requiring treatments [1,2,3,4]. This significantly decreased cytotoxicity of compound 1a towards normal SF cells, while still maintaining the anticancer activity towards Hep2 cells is an interesting feature. The aziridinyl moiety within the analogues served an important alkylation group [18], but the cytotoxic effects of the synthetic analogues towards carcinoma cells might not solely be due to the aziridinyl moiety, as the quinone structure is common in numerous natural products that are associated with antitumor activities [20].

Results

Conclusion