Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line

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Abstract

A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16ae), or 6 (2af) or disubstituted at positions 2 and 6 (4ac) or 2 and 8 (17ae) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with resistance index (RI) in the range 1–3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log kIAM) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.

Derivatives of 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones (structures A and B) have been synthesized and evaluated for their cytotoxicity against murine leukemia and human leukemia sensitive and MDR cell lines.

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Introduction

The prolonged clinical use of chemotherapeutic agents often causes the appearance of multidrug resistance (MDR) toward numerous antitumor compounds. This effect currently constitutes one of the major problems in clinical chemotherapy and has not yet been successfully solved.1, 2, 3 Many efforts have been directed toward the search for new antitumor anthracenedione derivatives with increased effectiveness against MDR tumor cell lines. This has resulted in the design of anthrapyrazoles4 and their aza-analogues,5 benzoperimidines6 and anthrapyridones,7 which fulfill this requirement. Recently we postulated that the presence of a heterocyclic ring condensed with the anthracenedione or with the structurally related acridone chromophore determines cytotoxic activity toward the multidrug resistant cell lines.6 Although the presence of a fused heterocyclic ring seems to be essential for overcoming MDR, the cytotoxic potency depends on the structure of the side chains and other substituents.

In this paper, we describe the synthesis and biological evaluation of a new group of anthracenedione derivatives with a pyridazone ring incorporated into the chromophore, namely 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones (hereafter referred to as anthrapyridazones), to determine the relationships between structure and antitumor activity of derivatives of this novel group. A series of compounds bearing [(alkylamino)-alkyl]amino side chain attached at positions 2, 6 or 8 to the chromophore moiety has been obtained. The presence of a second basic side chain could increase not only the binding to DNA, but also modify the physicochemical properties and solubility of the above derivatives and enhances their cytotoxic activity. Therefore, the 2,6- as well as the 2,8-disubstituted analogues have been synthesized (Fig. 1).

As evidenced earlier, the presence of hydroxyl groups in related ring systems such as anthracenediones,8 anthrapyrazoles,9 benzoperimidines6 and acridine derivatives10 increases antitumor activity in these classes of compounds. For this reason the 2,7-dihydro-3H-dibenzo [de,h]cinnoline-3,7-dione derivatives with hydroxyl groups at positions 8 and 11 have also been prepared.

Section snippets

Chemistry

The synthetic pathways leading to anthrapyridazone derivatives are shown in Scheme 1, Scheme 2, Scheme 3, Scheme 4. The starting materials 6-chloro- and 8-aminoanthrapyridazone (1 and 15), used in the synthesis of Figure 1, Scheme 1, Figure 1, Scheme 1, Figure 1, Scheme 3 and Figure 1, Scheme 3, were obtained by previously reported methods11, 12 by treatment of the respective acid chlorides of 5 or 15 with hydrazine. We prepared the 2-methyl-8-aminoanthrapyridazone (20) in an analogous way in

Cytotoxic activity

The anthrapyridazone derivatives were evaluated for their cytotoxic potency in vitro using the sensitive leukemia cell lines: murine L1210 and human K562 as well as human leukemia multidrug resistant subline K562/DX.

Mitoxantrone (MIT) and Doxorubicin (DX) were used as reference compounds. The cytotoxicity data are presented in Table 2 as IC50 values.

Most of the studied anthrapyridazones demonstrated high cytotoxic activity against L1210 leukemia. The 2,6-disubstituted derivatives (Figure 1,

Chemistry

Melting points, determined with a Boeticus PHMK05 apparatus, are uncorrected. Analyses are within±0.4% of the theoretical values and were carried out on a Carlo Erba CHNS-O-EA1108 instrument for C, H, N. A Beckman 3600 spectrophotometer was used for UV spectral determination. IR spectra were recorded on a UR 10 Zeiss spectrometer in KBr pellets; 1H NMR spectra were taken on a Varian 300-MHz or 500-MHz spectrometer using tetramethylsilane as an internal standard. The following NMR abbreviations

Acknowledgements

The authors acknowledge the financial support of these studies by the State Committee for Scientific Research (KBN), Warsaw, Poland (Grant No. 4 PO5F 035 19), and in part by Italian Ministry of Foreign Affairs, and the Chemical Faculty Gdańsk University of Technology, Poland. We also thank Dr. H. Kuśnierczyk for the in vivo tests.

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