Original article Imidazopyridine-fused [1,3]-diazepinones: Synthesis and antiproliferative activity Audrey Gallud a, 1 , Ophélie Vaillant a, 1 , Ludovic T. Maillard a , Dominique P. Arama a , Joëlle Dubois b , Marie Maynadier a , Vincent Lisowski a , Marcel Garcia a , Jean Martinez a , Nicolas Masurier a, * a Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Universités Montpellier I et II, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France b Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France article info Article history: Received 20 December 2013 Received in revised form 17 January 2014 Accepted 18 January 2014 Available online 30 January 2014 Keywords: Imidazo[1,2-a]pyridine Polyfused heterocycles Diazepinones Antitumor activity HGK inhibitors abstract A series of 15 pyrido-imidazo-1,3-diazepin-5-ones and pyrido-1,3-diazepine-2,5-diones were synthe- sized and their anticancer activities were evaluated. Among tested compounds on a cell lines panel, compound 6a presents the best growth inhibition activity on 21 cell lines with a cytotoxic effect on MDA- MB-435 melanoma cells. This compound led to deep cell morphological changes and revealed to be an inhibitor of the Hepatocyte progenitor kinase-like kinase (HGK), which is known to be implicated in the migration, adhesion and invasion of various tumor cells. Ó 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction Cancer is a notably complex, widespread and lethal disease ac- counting for 7.6 million deaths (around 13% of all deaths) in 2008, that is projected to continue rising, with an estimated 13.1 million deaths in 2030 [1]. Several lines of evidence support the view that chemotherapy has become one of the most significant treatment modalities in cancer management. Classical chemotherapy using small molecules or bioactive natural products is still the mainstay of chemotherapy, whereby the major cellular targets are DNA, tubulin [2,3], along with various kinases [4]. However, the absence of selectivity and acute toxicity of many antitumor agents beside the development of cellular drug resistance have been the major drawback in their usage, prompting the search for new more se- lective, efficient, and safe antitumor agents [5]. Azepine core is considered as a privileged structure to access to active compounds displaying a wide range of pharmacological activities. In particular, polyfused azepine derivatives led to the discovery of compounds with anticancer potency. Pyrrolo[1,2-c] [1,3]benzodiazepines (Fig. 1) revealed to be cytotoxic for Jurkat and neuronal cells, with induction of DNA cleavage [6]. Hymenialdisine, a marine natural product, which also has a pyrrolo-azepine core, is a potent inhibitor of cyclin dependent kinases (CDK) [7]. Paullone derivatives, which are based on the indolo[3,2-d][1]benzazepinone system, are CDK inhibitors with very potent antitumor activity [8,9]. Kenpaullone, alsterpaullone and their analogs were also re- ported to be inhibitors of glycogen synthase kinase-3 (GSK3) [10e 17] and of Hepatocyte progenitor kinase-like kinase (HGK) [18]. Moreover, some structural isomers of paullones, based on the indolo[2,3-d][2]benzazepinone framework, were reported to inhibit tubulin polymerization [19]. Recently, we reported an efficient approach to access polyfused diazepinone derivatives, based on the imidazo[1,2-a]pyridine (IP) nucleus, an aza analog of indole [20,21]. In continuation to this study and since some polyfused IP derivatives have been described to possess antitumor activities [22,23], we decided to evaluate the pharmacological potency of IP-fused diazepinones. We reported herein the synthesis of some pyrido-imidazo [1,3]diazepin-5-ones * Corresponding author. Tel.: þ33 4 11 75 96 42; fax: þ33 4 1175 96 41. E-mail address: nicolas.masurier@univ-montp1.fr (N. Masurier). 1 These authors contributed equally to the work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2014.01.044 European Journal of Medicinal Chemistry 75 (2014) 382e390