title: Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.
abstract: Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Serda
authors.affiliation: Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rasko
authors.affiliation: Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Potůčková
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland; A. Chełkowski Institute of Physics and Silesian Interdisciplinary Centre for Education and Research, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Mrozek-Wilczkiewicz
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Musiol
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Małecki
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Mieczysław
authors.initials: M
authors.lastname: Sajewicz
authors.affiliation: A. Chełkowski Institute of Physics and Silesian Interdisciplinary Centre for Education and Research, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Ratuszna
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Mazovia, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Department of Immunology, Medical University of Warsaw, Warsaw, Mazovia, Poland; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Mazovia, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Gołąb
authors.affiliation: Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Simůnek
authors.affiliation: Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Institute of Chemistry, University of Silesia, Katowice, Silesia, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Polanski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007501:Iron / Q000737:chemistry; D010084:Oxidation-Reduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013882:Thiosemicarbazones; D007501:Iron; D001205:Ascorbic Acid