Synthesis and biological activities of transition metal complexes based on acetylsalicylic acid as neo-anticancer agents.
[(μ(4)-η(2))-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure-activity study: Co(2)(CO)(6) was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE(2)) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co(4) and Prop-ASS-Ru(3) correlated well with apoptosis induction.
Rubner
Gerhard
G
Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, 14195 Berlin, Germany.
Bensdorf
Kerstin
K
Wellner
Anja
A
Kircher
Brigitte
B
Bergemann
Silke
S
Ott
Ingo
I
Gust
Ronald
R
D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002070:Butadienes / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007501:Iron; D012428:Ruthenium; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000480:Alkynes; D000970:Antineoplastic Agents; D002070:Butadienes; D056831:Coordination Complexes; D016861:Cyclooxygenase Inhibitors; D016718:Arachidonic Acid; D003035:Cobalt; D012428:Ruthenium; D007501:Iron; D015232:Dinoprostone; D001241:Aspirin