Original article Design and synthesis of new pyranoxanthenones bearing a nitro group or an aminosubstituted side chain on the pyran ring. Evaluation of their growth inhibitory activity in breast cancer cells George Kolokythas a , Ioannis K. Kostakis a , Nicole Pouli a , Panagiotis Marakos a, * , Olga Ch. Kousidou b , George N. Tzanakakis c , Nikos K. Karamanos b a Division of Pharmaceutical Chemistry, Department of Pharmacy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece b Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece c Department of Histology, Medical School, University of Crete, 71110 Herakleion, Greece Received 6 October 2006; received in revised form 30 October 2006; accepted 30 October 2006 Available online 4 December 2006 Abstract Some new 2,6-disubstituted pyrano- and 1,2-dihydropyrano[2,3-c]xanthen-7-ones have been synthesized and their antiproliferative activity has been evaluated against MDA-MB-231 breast cancer cells. The antiproliferative activity evaluation of the compounds provided evidence that a dimethylamino substituted side chain and the presence of 1,2 double bond play a key role in cell growth inhibition. Among the tested derivatives the 6-dimethylaminoethylamino-2-nitropyranoxanthenone analogue possessed a significant inhibitory effect in a wide range of concentrations. Ó 2006 Elsevier Masson SAS. All rights reserved. Keywords: 1,2-Dihydropyrano[2,3-c]xanthenones; Breast cancer cells; Growth inhibitory effect 1. Introduction It has been previously shown that dialkylaminoalkyl groups present in the side chains of the anthracenedione antitumor drugs mitoxantrone and ametantrone (Fig. 1) play a key role in their biological activity, regulating DNA binding after met- abolic activation [1]. The cytotoxic effects of the anthracene- diones, similar to anthracyclines, are probably multimodal, although interaction with DNA and consequent damage are thought to be essential for their therapeutic effect [2]. Numer- ous anthracenedione derivatives have been synthesized in the past ten years, in an attempt to obtain new active drugs, showing better therapeutic efficacy, together with fewer and less pronounced side effects, e.g. cardiotoxicity and the devel- opment of resistance [3e5]. The chemical modification of the anthracenedione chromophore unit, the repositioning of the hydroxyl substituents and the variation of the alkylamino side chains have been extensively investigated and resulted in the preparation of very active derivatives, exemplified by the heterocyclic bis(2-aminoethyl)amino-substituted com- pound pixantrone dimaleate (Fig. 1) endowed with antileuke- mic activity comparable to mitoxantrone. Pixantrone showed no measurable cardiotoxicity and is currently undergoing phase III clinical trials for the treatment of non-Hodgkin’s lymphoma [6e8]. All the above mentioned anthracenedione derivatives while being effective DNA intercalators, also inter- fere with the function of the DNA binding enzymes, such as DNA topoisomerases and DNA polymerases [9]. A common * Corresponding author. Tel.: þ30 210 7274830; fax: þ30 210 7274747. E-mail address: marakos@pharm.uoa.gr (P. Marakos). 0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2006.10.018 European Journal of Medicinal Chemistry 42 (2007) 307e319 http://www.elsevier.com/locate/ejmech