Synthesis and analytics of new anticancer platinum complexes

Since the discovery of the tumour inhibiting properties of cisplatin and its successful introduction in the clinic only a second platinum-based anticancer compound, carboplatin, is routinely used in the clinic world-wide. Oxaliplatin, a representative of the third generation platinum drugs is in clinical use in some countries. It is now registered for use in advanced colorectal cancer in Japan and some European countries (France, UK). It is the only platinum complex to have shown activity against this type of cancer. The synthesis and analytical characterization of novel anticancer platinum compounds is the major goal of the proposed project. This includes a novel concept for the preparation of platinum based drugs, the investigation of both tumour-inhibiting properties and modes of action of platinum(II)- and platinum(IV) compounds prepared in accord with the project. In detail the following classes of platinum based coordination compounds should be synthesized in accord with the project: 1.) New oxaliplatin analogues 2.) New platinum(II) and platinum(IV) complexes which are activated by low pH values 3.) New multinuclear platinum compounds 4.) New platinum compounds linked to glutamine The synthesized compounds will be tested in vitro and in vivo with regard to their tumour inhibiting properties. Moreover, hydrolysis, reduction and binding behaviour to 5`-GMP, oligonucleotides, DNA and other biomolecules should be investigated in detail to understand their mechanism of action.

In accord with the project, new tumor inhibiting platinum complexes should be synthesized and their behavior towards biological relevant molecules investigated. Furthermore, it was planned to evaluate their activity in representative human cancer cell lines; most promising candidates should be identified and tested for their anticancer properties in animal models. Biological relevant data such as the stability of the complexes in aqueous media or their lipophilicity should be determined as well. During the duration of the project, two classes of platinum complexes could have been synthesized and optimized with respect to their structure-activity relationships. Especially, synthesis of novel oxaliplatin analogues is thereby to be pointed out. Oxaliplatin (or Eloxatin TM ), a third generation platinum drug, is used very efficiently in the clinics as standard treatment in the case of metastatic colorectal cancer. Due to a selective derivatization of oxaliplatin (more precisely at the cyclohexanediamine ligand), it was possible to prepare new analogues, displaying a remarkable cytotoxic activity in human tumor cell lines. Additionally, some representatives were found to be better tolerable in animal experiments compared to oxaliplatin with respect to the general toxicity. During the project, a series of platinum compounds (more precisely bis(aminoalcoholato)platinum(II) complexes) have been synthesized, showing both, an increased reactivity towards DNA model nucleotides as well as an improved activity in cancer cell lines under slightly acidic conditions (pH value = 6). Under normal (physiological) conditions at a pH of 7.4, the complexes were equipped with a significantly reduced reactivity and biological activity. This is remarkable due to the fact that many solid tumors display an acidic milieu (pH up to a value of 5.5), which is explainable by an oxygen deficiency, resulting in an anaerobic metabolism. Furthermore, it is expected that the low reactivity of the complexes at pH 7.4 will contribute to a better tolerability in vivo. Results of the project were made available to the broad scientific community: 16 manuscripts were published, 26 posters were presented and 6 lectures were given.