Synthesis and cytotoxic activity of carboxamide derivatives of benzo[b][1,6]naphthyridin-(5H)ones
Graphical abstract
Twenty-six new compounds were prepared and tested. Compound 2t (R = 6-Me, X = 4-FC6H4, Y = (CH2)2NMe2) at 1.8 mg kg−1 was curative against colon 38 tumors in mice.
Introduction
The investigation of topoisomerase poisons as potential anticancer agents continues to be of interest. Tricyclic chromophores bearing a flexible cationic side chain make up one subclass, typified by the acridine-4-carboxamides (e.g., DACA, 11, 2). With respect to DACA, it has been found that the peri arrangement between the amide function and the central ring nitrogen is essential for anticancer activity.1 We recently reported that carboxamide derivatives of the benzo[b][1,6]naphthyridine system were topoI/II inhibitors and potent cytotoxins, and initial in vivo testing against subcutaneous colon 38 tumors in mice showed that, for example, a single dose (3.9 mg/kg) of compound 2c was curative.3 This encouraging result prompted us to further investigate this series; in particular, the synthesis allows a wide variation in the nature of the 2-substituent. We report here the preparation of an extended series of such derivatives, along with some variations in benzo-ring substituents and carboxamide side chain, their growth inhibitory properties against tumor cell lines and in vivo activity of selected examples.
Section snippets
Chemistry
The general synthetic scheme is that reported previously.3 The homophthalic acid analogues 3a–d were prepared by adapting a method for the pyridine example.4 Analogue 3e was prepared from 2-aminonicotinaldehyde and diethyl 1,3-acetonedicarboxylate by the method reported for the dimethyl analogue.5 Reaction of 3 with Vilsmeier reagent gave the key intermediates 4 (Scheme 1).6 In our previous paper,3 compounds 4a and 4b were reacted with a limited selection of amines under generally very mild
Conclusions
The 4-N-[2-(dimethylamino)ethyl]-2-substituted-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxamides are confirmed as a class of potent antitumor agents, with some showing curative in vivo activity in the sc colon 38 model in a single dosing protocol. In particular, the 2-(4-fluorophenyl) and 2-methyl derivatives provide promising candidates to further investigate efficacy and mechanism of action.
Experimental
NMR spectra were recorded on a Bruker Avance 300 spectrometer, operating at 300.13 MHz (1H) and 75.47 MHz (13C), and a Bruker DRX-400 spectrometer operating at 400.13 MHz (1H) and 100.62 MHz (13C). Chemical shifts are reported as δ values (ppm) relative to Me4Si. Standard PENDANT, HSQC, and HMBC spectra were used in making the NMR assignments. EI and LSI (3-nitrobenzyl alcohol as liquid matrix) mode high-resolution mass spectra were obtained by Dr. N. Davies, University of Tasmania, Australia.
Acknowledgements
M.L.R. is grateful for the award of an APRA.
References and notes (15)
- et al.
Bioorg. Med. Chem. Lett.
(2001) - et al.
NCI Cancer Treat. Rev.
(1980) - et al.
Eur. J. Cancer
(1996) - et al.
J. Med. Chem.
(1987) - et al.
Cancer Chemother. Pharmacol.
(1995) - et al.
J. Med. Chem.
(2003) - et al.
J. Chem. Soc., Perkin Trans. 1
(1972)
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2015, Chinese Chemical LettersCitation Excerpt :They are associated with a wide spectrum of biological activities such as anticancer [4], anti-HIV-1 [5], antimicrobial [6] and cytotoxic activity [7]. Therefore, the synthesis of [1,6]naphthyridine derivatives has aroused great interest in organic and medicinal communities [8–12]. On the other hand, benzofuran derivatives have attracted widespread interest in view of their presence in natural products, and their biological and pharmacological activities [13].
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2014, TetrahedronCitation Excerpt :In continuation of these studies, we now describe facile route to the synthesis of 4-amino-N-benzylbenzo[b][1,8]naphthyridin-2(1H)-ones starting from N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides. The required N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides/propionamide 2a–i and N-alkyl-N-(3-cyanoquinolin-2-yl)acetamides 2j–m were prepared in two steps, firstly, amination of 2-chloroquinoline-3-carbonitriles with aliphatic primary amines9h followed by acetylation reaction with 2 mL of acetic/propionic anhydride and 3 equiv of KOH at 120 °C in good yields (Scheme 1, Table 2). We next examined the reaction conditions for cyclization of substrates 2 using different bases and solvents to afford the synthesis of benzo[b][1,8]naphthyridine framework.