Development of anticancer platinume(IV) complexes

Three platinum-based anticancer metal complexes, cisplatin, carboplatin and oxaliplatin, are in world-wide clinical use in the fight against cancer. In this context it is worthwhile mentioning that about 50 % of all anticancer treatments are based on platinum compounds. Nevertheless, platinum chemotherapy is accompanied by severe side effects and acquired or intrinsic resistance of the cancer cells. Furthermore, it is, in contrast to cis-, carbo-, and oxaliplatin, which are given intravenously, desirable to develop drugs which can be administered orally in order to reduce hospitalization costs and to increase patients` quality of life. These limitations led to an immense search for new platinum analogs. Among them were also orally absorbable platinum(IV) complexes like satraplatin, which is now in advanced phase III clinical trials. Additionally, development of platinum(IV) complexes is of high interest from the chemical point of view since they are kinetically inert and consequently accessible for derivatization at peripheral functional groups. This is in clear contrast to the chemistry of the respective platinum(II) counterparts now opening up the possibility to prepare novel and promising candidates for anticancer chemotherapy. The aim of the project is to develop new anticancer platinum(IV) complexes via derivatization of peripheral function groups. In detail, the following points should be taken into consideration in accordance with the present project: (i) Synthesis of platinum(IV) complexes via derivatization of peripheral functional groups (especially COOH) and in detail spectroscopic characterization (ii) Evaluation of their cytotoxic and anticancer potential in vitro and in vivo (iii) Determination of their reduction potential, lipophilicity and cellular accumulation (iv) Investigation of their interactions with important biomolecules and studies about their behavior in cancer cell extracts deriving from cisplatin sensitive and resistant cell lines. (v) Optimization of structure-activity relationships

Since decades, tumor inhibiting platinum compounds have been used successfully in every second chemotherapy in the fight against cancer. The therapy is accompanied, at least in part, by severe side-effects; additionally platinum-based chemotherapy has to be administered intravenously. This leads to reduced acceptance of therapy and to considerable hospitalization costs. Consequently, it was the aim of the research work to develop novel, less reactive platinum complexes, to evaluate their activity in human cancer cells, to investigate their mode of action and to setup, optimize and, if possible, predict respective structure-activity relationships.Octahedrally configured platinum compounds of the oxidation state +4 show little reactivity compared to those derivatives approved in the clinics. Therefore, they feature a different profile of side-effects and can be administered orally given an appropriate lipophilicity. Today none of these platinum complexes is approved, although five representatives have been evaluated in patients. Within the project work, a series of novel platinum(IV) complexes could be synthesized, characterized in detail and investigated in different human cancer cell lines with respect to their activity (cytotoxicity). Via controlling the lipophilicity, new compounds with remarkable cytotoxicity could be obtained. Lipophilicity as well as accumulation of representative complexes in tumor cells was investigated. As could be demonstrated, the cellular uptake was clearly dependent on the lipophilic properties. Less reactive platinum complexes of the oxidation state +4 are reduced in the organism into their considerably more reactive platinum analogs of the oxidation state +2; they act as so-called prodrugs. Therefore, the reduction (transformation of the oxidation state from +4 to +2) of representative compounds was investigated in the presence of vitamin C and aqueous extracts of cancer cells. Significant differences of the reduction behavior in dependency on the type of ligand bound to the metal center were found. All evaluated parameters were used as basis for a theoretical model which could now be used, at least within compound classes, for robust prediction of cytotoxic properties (also known as QSAR = quantitative structure-activity relationships).Concluding, it has to be stated, that based on the support by the FWF, important contributions to the elucidation of the mode of action as well as to the development of clinically relevant anticancer platinum complexes could be made.