Synthesis and Antiproliferative Activity of Metal-Based

Quinolin-2(1H)-one backbone is involved in a large number of biologically active compounds. Cytotoxic activity of a-methylidene--butyrolactones bearing quinoline, coumarin, flavone, xanthone, and quinolin-2(1H)-one heterocycles was studied, showing that quinolin-2(1H)-one derivatives were the most potent antiproliferative agents. From the other side, the indole moiety is a basic structural element of clinically used anticancer drugs, e.g. vinblastine, vincristine. Indolo[3,2-c]quinolines, the main object of the study in this project, show structural similarity to indolo[3,2- d]benzazepines, e.g. kennpaullone, a moderate inhibitor of cyclin dependent kinases (CDKs), and therefore a good candidate for futher structural optimisation, guided in part by understanding of the ATP binding site in CDKs. Structural diversity which will be achieved by derivatisation of this class of compounds at different positions of the original skeleton (positions 2, 6, 8 and 11) and metallation, will enable to establish novel structure-cytotoxicity relationships. Refinement of the structure will be combined with continuous biological screening and feedback in order to create a potent antitumour drug in terms of activity in vitro. In addition, the effect of the seven-membered azepine ring folding in metal-free and metal-based indolo[3,2-d]benzazepines on the antiproliferative activity will be elucidated. The first steps towards the understanding the underlying biological mechanisms of cytotoxicity (cell uptake and intracellular drug localization by optical fluorescence imaging) of metal-based indolo[3,2-c]quinolines will be undertaken. The proposal brings together inorganic and organic chemists, and biologists that have complementary experise in the area of development of novel drugs. In particular, the effect of metallation of paullone compounds on the antiproliferative activity and cell cycle progression, which was unexplored in the past, has been currently studied by us (see Inorg. Chem. 2006, 45, 1945-1950; Inorg. Chem. 2007, 46, 3645-3656; J. Med. Chem. 2007, 50, 6343- 6355 and Organometallics 2007, 26, 6643-6652). The results reported form a sounder basis for successful performing of this research proposal.

Quinolin-2(1H)-one backbone (Chart 1, left) is involved in a large number of biologically active compounds. Cytotoxic activity of -methylidene--butyrolactones bearing quinoline, coumarin, flavone, xanthone, and quinolin-2(1H)-one heterocycles was studied, showing that quinolin-2(1H)-one derivatives were the most potent antiproliferative agents. From the other side, the indole moiety (Chart 1, right) is a basic structural element of clinically used anticancer drugs, e.g. vinblastine, vincristine. Chart 1 N ON HH Indolo[3,2-c]quinolines, the main object of the study in this project, combining both structural units depicted in Chart 1, show structural similarity to indolo[3,2-d]benzazepines, e.g. kennpaullone (Chart 2), a moderate inhibitor of cyclin dependent kinases (cdks), and therefore a good candidate for further structural optimisation, guided in part by understanding of the ATP binding site in cdks. Structural diversity has been achieved by derivatisation of this class of compounds at different positions of the original skeleton (positions 2, 4, 6 and 8) and metallation, enabling establishment of novel structure-cytotoxicity relationships. In particular, it has been shown that substitution of the seven-membered azepine ring in metal- free and metal-based indolo[3,2-d]benzazepines by a flat six-membered N-containing ring in indolo[3,2-c}quinolones resulted in a strong enhancement of antiproliferative activity in human cancer cell lines. The first steps towards the understanding the underlying biological mechanisms of cytotoxicity (cell uptake and intracellular drug localization by optical fluorescence imaging) of metal-based indolo[3,2-c]quinolines have been also undertaken. Chart 2 The proposal which brought together inorganic and organic chemists, and biologists that have complementary expertise in the area of development of novel drugs has delivered six original publications and two review articles and considerably improved our knowledge about indolo[3,2-c]quinolines and their metal-based derivatives as potential anticancer drugs.