Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities.

Shu-Qin Qin,Lian-Chun Li,Dian-Peng Li,Hai-Yun Li,Jing-Ru Song

doi:10.3390/molecules24030437

Abstract

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC50 values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC50 values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC50 value of 1.13 μM.

Highlights

Nowadays, cancer is a major public health issue in most of countries with high mortality rates [1–3].it is necessary and urgent to develop novel antitumor drugs with higher activity but lower toxicity
Natural occurring nitidine, fagaronine, chelerythrine, and sanguinarine exhibit good antitumor activity. The synthesis of their derivatives is of great interest because of the lower activity in vivo owing to the instability of the iminium salt moiety in the structure [10–12]
Protected benzamides 5b, 5e, 5h, and 5k were treated with TFA to afford the phenanthridinone derivatives 6a-6d, while N-MOM protected benzamides 5c, 5f, and 5i were treated with LiAlH4 to provide planar phenanthridine derivatives 7a–c

Summary

Introduction

It is necessary and urgent to develop novel antitumor drugs with higher activity but lower toxicity. Natural occurring nitidine, fagaronine, chelerythrine, and sanguinarine exhibit good antitumor activity. The synthesis of their derivatives is of great interest because of the lower activity in vivo owing to the instability of the iminium salt moiety in the structure [10–12]. As a synthetic derivative of benzo[c]phenanthridine, NK 314 displays high antitumor activity in vitro and in vivo and can be regarded as a promising anticancer drug which inspired chemist to develop more structurally modified or structurally simple alternatives [13–16]

Methods

Results

Conclusion