Elsevier

Bioorganic & Medicinal Chemistry

Volume 15, Issue 4, 15 February 2007, Pages 1651-1658
Bioorganic & Medicinal Chemistry

Synthesis, cytotoxicity, and DNA topoisomerase II inhibitory activity of benzofuroquinolinediones

https://doi.org/10.1016/j.bmc.2006.12.012Get rights and content

Abstract

Benzofuroquinolinediones (7c and 7d) were synthesized by base-catalyzed condensation of dichloroquinolinediones with phenolic derivatives. Their dialkylaminoalkoxy derivatives (8i8p) were prepared by reaction with various dialkylaminoalkyl chlorides. The cytotoxicity of the synthesized compounds was evaluated against eight types of human cancer cell lines, and their topoisomerase II inhibition was assessed. In general, the cytotoxicity of benzofuroquinolinediones (8i8p) was similar or superior to that of doxorubicin and showed more potent inhibitory activity than naphthofurandiones (8a8h). Also, most of the compounds exhibited excellent topoisomerase II inhibitory activity at a concentration of 5 μM and two compounds, 8d and 8i, showed IC50 values of 1.19 and 0.68 μM, respectively, and were much more potent than etoposide (IC50 = 78.4 μM), but similar to doxorubicin (IC50 = 2.67 μM). However their inhibitory activity on topoisomerase I was lower, and 8d and 8i showed IC50 values of 42.0 and 64.3 μM, respectively.

Introduction

Many of the important chemotherapeutic drugs presently in clinical use have been recognized to exert their activity by interfering with the DNA. Compounds containing a planar chromophore with two to four fused aromatic rings act as DNA intercalator, which causes enzyme blockade and reading errors during the replication process. A tetracyclic structural pattern consisting of a benzene ring attached to the 2-position of a naphthalene nucleus or heterocyclic ring moiety was observed among these compounds, and known as 2-phenylnaphthalene-type structural pattern hypothesis. For example, a pentacyclic alkaloid, camptothecin 1, is a potent antitumor agent against numerous types of cancers.1 WS-5995A 2 is active against L1210 leukemic cells,2 and a natural plant alkaloid, ellipticine 3, is an anticancer drug.3 Compound 4 was reported to be active against human leukemia cells (HL-60) and small-cell lung cancer (SCLC)4 (Fig. 1).

The cytotoxic mechanisms of coplanar annulated polycyclic compounds have been shown to consist of intercalation5 in human DNA and further, modification of topoisomerases. Topoisomerase I and II are essential enzymes in the regulation of DNA topology and supercoiling, which are crucial for transcription and replication.

Topoisomerase I (topo I) breaks one of the DNA strands and the DNA can then unwind by revolving about the remaining phosphodiester bond to remove supercoils. The enzyme then relegates the break to restore the DNA with an altered linking number. The only topo I inhibitors to have undergone clinical trials as antitumor drugs are camptothecin 1 and its structural derivatives.

Topoisomerase II (topo II) is an enzyme that catalyzes changes in the topology of DNA via a mechanism that involves the transient double-strand breaking and rejoining of phosphodiester bonds. This enzyme plays several key roles in DNA metabolism and chromosome structure, and it is the primary molecular target for a number of potent anticancer drugs such as etoposide.6 Topo II inhibitors display great structural diversity and are widely used as antitumor agents, and six topo II cleavable complex inhibitors (Etoposide, Teniposide, Doxorubicin, Daunorubicin, Idarubicin, and Mitoxantrone) have been approved for clinical use. Recently, topo II inhibitors have created a great deal of interest in the design of new antitumor agents.7, 8, 9, 10

The derivatives of benzonaphthoquinolindione 4 have a suitable structure possessing the coplanar conformation and were reported to have cytotoxicity and topoisomerase II inhibitory activity.4 In our continuous effort in development of novel DNA intercalators based on nitrogen-containing heterocyclic ring with a para-conjugated quinone structure, we synthesized the benzofuroquinolinedione analogues and their cytotoxicity against the eight human tumor cell lines and inhibitory activity against topo I and II are reported in this study. Also some benzonaphthofurandiones were prepared to compare the cytotoxic activity.

Section snippets

Chemistry

Condensation of 5 (2,3-dichloronaphthalene-1,4-dione 5a or 6,7-dichloroquinoline-5,8-dione 5b) and 6 (resorcinol 6a or 4-chlororesorcinol 6b) was achieved with modification of the reported reaction conditions.4, 11 Treatment of compounds containing the hydroxyl group with dialkylaminoalkyl chloride in base and phase transfer catalysis (PTC, benzyltriethylammonium chloride) gave the corresponding dialkylaminoalkoxy derivatives, as shown the Scheme 1. Benzonaphthofurandiones (7a and 7b) were

Conclusion

The benzonaphthofurandione and benzofuroquinolinedione derivatives were synthesized by base-catalyzed condensation. The cytotoxicity of the benzofuroquinolinedione derivatives was as high as that of doxorubicin and higher than that of the corresponding naphthoquinone analogues. The compounds with dimethylaminoisopropoxy group especially showed excellent inhibitory activity throughout the entire in vitro test. Most of the test compounds showed high activity on topo II at a concentration of 5 μM,

Synthesis

All melting points were taken in Pyrex capillaries using electrothermal digital melting point apparatus (Büchi). 1H NMR spectra were recorded on a 400 MHz Varian FT-NMR spectrometer using tetramethylsilane as an internal standard. Samples were dissolved in CDCl3 or DMSO-d6. Mass spectra were obtained on the Mass spectrometer JMS-700 (Jeol, Japan) at the Korea Basic Science Institute (Seoul). Most of the reagents were purchased from Sigma–Aldrich Chemical Company.

Cytotoxicity and topoisomerase inhibitory assay

Trichloroacetic acid (TCA) and

Acknowledgment

This work was supported from the Korea Research Foundation (KRF-2005-005-J01501).

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