Synthesis and characterization of quinoline-based thiosemicarbazones and correlation of cellular iron-binding efficacy to anti-tumor efficacy Maciej Serda a , Danuta S. Kalinowski b,⇑ , Anna Mrozek-Wilczkiewicz a,c , Robert Musiol a , Agnieszka Szurko c,d , Alicja Ratuszna c , Namfon Pantarat b , Zaklina Kovacevic b , Angelica M. Merlot b , Des R. Richardson b,⇑ , Jaroslaw Polanski a,⇑ a Department of Organic Chemistry, Institute of Chemistry, University of Silesia, PL-40006 Katowice, Poland b Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia c Department of Solid State Physics, Institute of Physics, University of Silesia, PL-40007 Katowice, Poland d Department of Experimental and Clinical Radiobiology, Center of Oncology, M. Sklodowska-Curie Memorial Institute, PL-44101 Gliwice, Poland article info Article history: Received 14 May 2012 Revised 5 July 2012 Accepted 6 July 2012 Available online 15 July 2012 Keywords: Anti-tumor activity Desferrioxamine Iron chelation abstract Iron chelators have emerged as a potential anti-cancer treatment strategy. In this study, a series of novel thiosemicarbazone iron chelators containing a quinoline scaffold were synthesized and characterized. A number of analogs show markedly greater anti-cancer activity than the ‘gold-standard’ iron chelator, des- ferrioxamine. The anti-proliferative activity and iron chelation efficacy of several of these ligands (espe- cially compound 1b), indicates that further investigation of this class of thiosemicarbazones is worthwhile. Ó 2012 Elsevier Ltd. All rights reserved. Iron (Fe) chelators are commonly used to treat diseases con- nected with altered iron metabolism, for example, b-thalassaemia major. 1 However, considering the marked anti-proliferative activ- ity of this group of agents, recent investigations have focused on the anti-cancer efficacy of iron chelators. 2,3 In fact, there are many reports of the anti-proliferative activity of desferrioxamine (DFO), Triapine Ò and other ligands based on the (thio)urea moiety. 2 The cytotoxic mechanisms of chelators include: (1) the inhibi- tion of cellular iron uptake from the iron-binding protein, transfer- rin (Tf); 4–7 (2) mobilization of iron from cells; 4–7 (3) the inhibition of the iron-containing enzyme involved in the rate-limiting step of DNA synthesis, ribonucleotide reductase; 8 and (4) the formation of redox-active iron complexes that generate reactive oxygen spe- cies (ROS). 5,7 The latter mechanism is significant, especially in the context of recent reports demonstrating the role of ROS generation in increasing the anti-proliferative activity of chelators against tumor cells. 5,7,9 Alterations in the metabolism of iron 10–13 and copper 14,15 are known to occur in cancer cells and may play a role in angiogene- sis 16 and metastasis. 17 The rationale behind the potential applica- tion of iron chelators for cancer treatment is due to the higher demand for iron in rapidly proliferating tumor cells in comparison to their normal counterparts. 10–12 The greater requirement for iron in tumor cells results in high levels of the transferrin receptor (TfR1) on the cell surface which binds Tf. 13 Furthermore, the expression of ribonucleotide reductase is markedly higher in neo- plastic cells relative to their normal counterparts. 2 Hence, this also increases the sensitivity of cancer cells to iron-depletion. Although DFO was investigated as an anti-cancer agent, interest in this compound was diverted in favor of more effective ligands such as aroylhydrazones that show greater iron chelation efficacy and cellular permeability. 3 Some of these compounds were shown to have moderate anti-tumor activity that was significantly greater than that of DFO for example, 2-hydroxy-1 naphthylaldehyde isonicotinoyl hydrazone (311; Fig. 1). 18,19 Further structural modi- fications of this series produced the 2-hydroxy-1-naphthylalde- hyde thiosemicarbazone (NT) 20 and di-2-pyridyl ketone isonicotinoyl hydrazone (PKIH) series 21 of chelators (Fig. 1), which showed superior activity. 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.07.030 Abbreviations: Bp44mT, 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; BpT, 2-benzoylpyridine thiosemicarbazone; DFO, desferrioxamine; DpT, dipyridyl thiosemicarbazone; Dp44mT, di-2-pyridyl ketone-4,4-dimethyl-3-thiosemicarba- zone; NT, 2-hydroxy-1-naphthylaldehyde thiosemicarbazone; PKIH, di-2-pyridyl ketone isonicotinoyl hydrazone; ROS, reactive oxygen species; Tf, transferrin; TfR1, transferrin receptor 1; QCIH, 2-quinolinecarboxaldehyde isonicotinoyl hydrazone; QT, quinoline thiosemicarbazone. ⇑ Corresponding authors. Tel.: +61 2 9036 6547; fax: +61 2 9351 3429 (D.S.K.); tel.: +61 2 9036 6548; fax: +61 2 9351 3429 (D.R.R.); tel./fax: +48 322599978 (J.P.). E-mail addresses: danuta.kalinowski@sydney.edu.au (D.S. Kalinowski), d. richardson@med.usyd.edu.au (D.R. Richardson), polanski@us.edu.pl (J. Polanski). Bioorganic & Medicinal Chemistry Letters 22 (2012) 5527–5531 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl