Novel metal-based Cdk inhibitors for anticancer therapy

Hyperproliferative disease states, including cancer, are characterized by the disturbed cell division cycle. In cancer chemotherapy for treatment of such disease states there are used compounds that modulate the cell cycle and can block/stop uncontrolled or unwanted cell proliferation. It is commonly accepted that the suppression of complete DNA replication is a main strategy for the induction of apoptosis in tumour cells. Therefore the top targets of cancer chemotherapy which leads to suppression of cell growth, DNA replication and mitotic transfer of the genome to new daughter cells are DNA itself or the regulator mechanisms, namely cyclin-dependent kinases (Cdks), responsible for DNA replication and in general the whole cell cycle. Among various cancer chemotherapeutic agents the platinum metal-based complexes have a special significance because of their targeted DNA binding by means of direct coordination of platinum metals to the nucleophilic nitrogens of the nucleobases. The presence of bond between platinum compound and DNA has negative consequences on the ability of the duplex to function as a template for replication and transcription, and at the same time is the desired event in cancer treatment. Modulation of Cdk activity because of the complex nature of their regulation is approached via multiple modes of therapeutic intervention. Organic chemistry traditionally dominated in medicinal chemistry offers a growing number of Cdk inhibitors represented by various chemical classes. But it can be extended by using metal complexes (inorganic compounds) which with their wide spectrum of coordination numbers, coordination geometries and redox activity offer novel mechanisms of action which are unavailable to organic compounds. The observed synergy of some Cdk inhibitors with platinum complexes (cisplatin) under drug combination therapy permits to suppose preserving or even enhancing after complexation their antitumour and Cdk inhibiting activity. Therefore the research is focusing on the investigation of the metalation effect on the biological properties of some potent Cdk inhibitors. It is proposed to combine the well recommended in cancer treatment platinum metals (M = Pt, Ru and Os) and imidazolyl pyrazole organic compounds (L = 3-(1H-benzimidazol-2-yl)-5-heteroaryl-pyrazolo 3,4-b pyridines, 3-(1H-benzimidazol-2-yl)-4-[2-(heteroaryl)-vinyl]-pyrazoles and 3-(1H-imidazol-2-yl)-4-[2- (heteroaryl)-vinyl]-pyrazoles; Cdk inhibitors and antiproliferatives) for the investigation of their complexes [MCl2 L], [MCl( 6 -p-cymene)L]Cl, [MCl2 L2 ], [ML 3 ]Cl 2 , [MCl2 (DMSO)2 L] as new potent antitumour candidates as well as the elucidation of the roles of both the metal and ligands in cytotoxic processes. Moreover the binding of organic ligands (L) to metal might serve as a means to increase their bioavailability.