Tumor-inhibiting bis(β-Diketonato) metal complexes. Budotitane, cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV)

Abstract

Cisplatin, cis-diamminedichloroplatinum(II), and carboplatin, cis-diammine(cyclobutane-1,1-dicarboxylato)platinum(II), are the first drugs from inorganic chemistry to have come under routine clinical use in medical oncology. Their antitumor activity ranges from testicular carcinomas, ovarian carcinomas, and tumors of the head and neck to bladder tumors. However, the spectrum of indication is fairly limited. There is no or only insufficient antitumor activity in tumors which account for the major share of cancer mortality today, e.g. lung tumors and gastrointestinal tumors. Direct derivatives of cisplatin such as carboplatin have only led to a limited reduction or change in drug toxicity. In most cases, the toxicity pattern has changed from nephrotoxicity to myelotoxicity. New metal complexes are now being developed which are designed to supplement the spectrum of indication of platinum complexes. Among non-platinum complexes, budotitane (INN), cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV), is among the most advanced. It is undergoing clinical trials today. Extensive investigations into structure-activity relations have clearly shown a dependence of the activity on the central metal and the diketonato ligand. The tumor-inhibiting effect decreases in the order titanium > zirconium > hafnium > molybdenum > tin > germanium. Antitumor activity is also highly dependent on the nature of the diketonate used. Ligands substituted with planar aromatic ring systems such as the phenyl groups in budotitane are advantageous. Most of the tumor-inhibiting bis(β-diketonato) complexes are cis-configurated. The cis-configurated compounds with an unsymmetrically substituted β-diketonate as ligand are in an equilibrium between three possible cis-isomers in solution at room temperature, due to the fact that the diketonate can rotate via a twist mechanism. The easily hydrolizable group in these complexes does not play a major role in antitumor activity, but it is important for the galenic formulation in the clinic. The ethoxy group as leaving group in budotitane hydrolizes at a slower rate than the corresponding halides.

The best antitumor effects could be obtained with titanium and a diketonato ligand substituted with phenyl groups. Budotitane is highly active in several transplantable tumors and shows promising effects in an autochthonous colorectal tumor model, which is highly predictive for the clinical situation. Side-effects include mild hepatotoxicity and nephrotoxicity. These findings have been confirmed in clinical phase I studies. A phase II study is now in preparation. If preclinical antitumor activity in colorectal tumors can be confirmed in the clinic, this would lead a considerable step forward in the chemotherapy of cancer.