Full Paper Synthesis, Characterisation and Biological Evaluation of Copper and Silver Complexes based on Acetylsalicylic Acid Gerhard Rubner 1 , Kerstin Bensdorf 1 , Anja Wellner 1 , Silke Bergemann 1 , and Ronald Gust 1,2 1 Institute of Pharmacy, Freie Universita ¨t Berlin, Berlin, Germany 2 Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria Metalcarbonyl complexes with ligands derived from acetylsalicylic acid demonstrated high cytotoxic potential against various tumor cell lines and strong inhibition of the cyclooxygenase enzymes COX-1 and 2. In this study we tried to achieve comparable effects with [alkyne]silver or copper trifluoromethanesulfonate complexes which are more hydrophilic then the uncharged metalcarbonyl derivatives. All compounds were evaluated for growth inhibition against breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1 and COX-2 inhibitory effects at isolated isoenzymes. Pure ligands showed neither cytotoxic nor COX-inhibitory effects. While the silver complexes of (but-2-ynyl)-2-acetoxybenzoate (But-ASS-Ag) and (but-2-yne-1,4-diyl)-bis(2- acetoxybenzoate) (Di-ASS-But-Ag) were strong cytostatics, only the copper complex Di-ASS-But-Cu was active. At the COX enzymes the complexes were more effective than their ligands and aspirin. Keywords: Acetylsalicylic acid / Copper / Cyclooxygenase / Cytotoxicity / Silver / Transition metal complexes Received: December 9, 2010; Revised: January 20, 2011; Accepted: January 20, 2011 DOI 10.1002/ardp.201000382 Introduction Despite the success of cisplatin and closely related platinum antitumor agents in tumor therapy [1, 2], there is an increasing interest in new transition metal antitumor drugs for the second line therapy. In our group, we focused our attention on the design of multi-target complexes. A specifically acting ligand was combined with a cytotoxic metal moiety. This drug design was successful regarding hormone-dependent tumors [3–8]. Our present drug design based on the observation that various tumor cells e.g. MCF-7 and MDA-MB 231 mammary carcinoma cells contain permanent or inducible amounts of cyclooxygenase enzymes 1 and 2 (COX-1, COX-2). Their growth can therefore be influenced by non-steroidal anti- inflammtory drugs (NSAIDs). While indometacin exerts high cytotoxicity acetylsalicylic acid (aspirin, ASS) was nearly inac- tive. The cell growth inhibitory effects can strongly be increased by esterification of ASS with propargylic alcohol and coordination of the alkyne to a Co 2 (CO) 6 cluster (Co-ASS) [9]. Co-ASS showed high COX inhibitory effects and another acetylation profile of COX enzymes than ASS. Structure activity relationship studies demonstrated a high relevance of an aspirin partial structure and the presence of a metal- carbonyl cluster for these effects [10, 11]. Using a cyclopentadienyl (Cp) moiety for the design of organometal complexes only the thallium complexes showed high cytotoxicity. Related Cp-metalcarbonyls were distinctly less active [12]. These finding induced us to synthesize further carbonyl-free organometal complexes and to evaluate their growth inhibitory potency. We decided to use in this pre- liminary study silver and copper alkynyl complexes with (but- 2-ynyl)-2-acetoxybenzoate (But-ASS) and (but-2-yne-1,4-diyl)- bis(2-acetoxybenzoate) (Di-ASS-But) already proven as suit- able ligands. The new complexes were tested for growth inhibition against MCF-7, MDA-MB 231 and HT-29 cells as well as for COX inhibitory effects at isolated enzymes (COX-1 and COX-2). Results and discussion Synthesis and Structural Characterisation The synthesis of But-ASS and Di-ASS-But were described else- where [11]. All organometalic syntheses were carried out under ‘‘Schlenk’’ conditions using an inert, dry atmosphere. Correspondence: Ronald Gust, Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. E-mail: ronald.gust@uibk.ac.at Fax: þ43 512 507 2940 684 Arch. Pharm. Chem. Life Sci. 2011, 344, 684–688 ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim