Metal complexes of indolo-quinolines, -benzazepines, -benzazocines and -benzazonines

Cancer is among the three leading causes of death worldwide, accounting for 7.6 million deaths in 2008 (13%). More people die only from infectious and cardiovascular diseases (27.5 and 30.5%, respectively). Therefore, the fight against cancer will continue to be a challenging issue for medicinal and biochemical research in the 21st century. This is intended to be a follow up proposal of the two previous FWF projects P20897-N19 and P22339-N19, the results of which were published as 15 full papers and 2 reviews in peer-reviewed journals. Briefly, highly cytotoxic metal complexesof bothmodified indolo[3,2- d]benzazepines and indolo[3,2-c]quinolines with IC50 values in nanomolar concentration range were prepared. The fact that the complexes are highly cytotoxic, at nanomolar concentrations, could allow their application at very low doses, which could offer a significant advantage over platinum-based chemotherapeutics. Structure-activity relationships have been significantly extended by creating proligand libraries based on both scaffolds. In particular, metal complexes with a flat modified indoloquinoline proved to be by one order of magnidude more cytotoxic to cancer cells than metal complexes with a folded inolobenzazepine also called paullone. In many cases coordination of proligands based on these two scaffolds to metal ions increased their antiproliferative activity and aqueous solubility, the latter property being of great importance for development of potential drug candidates. The paullone complexes with a derivatised lactam unit revealed higher antiproliferative activity than the complexes modified at position 9 of the scaffold. The metal binding site locus in indolo[3,2-c]quinolines proved to exert a marked influence on cytotoxicity. Unlike paullones, some metal-based indoloquinolines were found to possess intrinsic fluorescence enabling the study of the drug distribution in the tumour cells by fluorescence microscopy. This exciting results prompted us further structural optimisation of potential anticancer drugs by involving in the current study 8 new scaffolds of medical relevance. We would like to investigate the effects of replacement of 7-membered azepine ring in paullones by a 8- and 9-membered benzazocine and benzazonine, respectively, the locus of lactam unit in them and position of the indole basic unit vs lactam group on antiproliferative activity both in vitro and in vivo, as well as affinity to particular enzymes as possible targets for these potential anticancer drugs. Another issue to be elucidated is whether attachment of cell-penetrating homing peptides to highly cytotoxic scaffolds or nanoparticle drug formulations elaborated over the lifetime of the project can lead to their selective delivery to cancer cells and, consequently, markedly reduce the side effects. To achieve these ambitious goals the proposal brings together organic, inorganic and analytical chemists,biochemists, electrochemists,experts in massspectrometry, protein crystallography, molecular modeling and oncology.

Cancer is among the three leading causes of death worldwide, accounting for 7.6 million deaths in 2008 (13%). More people die only from infectious and cardiovascular diseases (27.5 and 30.5%, respectively). Therefore, the fight against cancer will continue to be a challenging issue for medicinal and biochemical research in the 21st century. This is a follow up proposal of the two previous FWF projects P20897-N19 and P22339-N19, the results of which were published as 15 full papers and 2 reviews in peer-reviewed journals. Briefly, highly cytotoxic metal complexes of both modified indolo[3,2-d]benzazepines and indolo[3,2-c]quinolines with IC50 values in nanomolar concentration range were prepared. The fact that the complexes are highly cytotoxic, at nanomolar concentrations, could allow their application at very low doses, which could offer a significant advantage over platinum-based chemotherapeutics. Structure-activity relationships have been significantly extended by creating proligand libraries based on both scaffolds. In particular, metal complexes with a flat modified indoloquinoline proved to be by one order of magnidude more cytotoxic to cancer cells than metal complexes with a bent indolobenzazepine also called paullone. In many cases coordination of proligands based on these two scaffolds to metal ions increased their antiproliferative activity and aqueous solubility, the latter property being of great importance for development of potential drug candidates. The paullone complexes with a derivatised lactam unit revealed higher antiproliferative activity than the complexes modified at position 9 of the scaffold. The metal binding site locus in indolo[3,2-c]quinolines proved to exert a marked influence on cytotoxicity. Unlike paullones, some metal-based indoloquinolines were found to possess intrinsic fluorescence enabling the study of the drug distribution in the tumour cells by fluorescence microscopy. This exciting results prompted us further structural optimisation of potential anticancer drugs by involving in the current study 8 new scaffolds of medicinal relevance. We investigated the effects of replacement of 7-membered azepine ring in paullones by a 8- and 9-membered benzazocine and benzazonine, respectively, the locus of lactam unit in them and position of the indole basic unit vs lactam group on antiproliferative activity both in vitro and in vivo, as well as affinity to particular enzymes as possible targets for these potential anticancer drugs. Achievement of the main goals of the research proposal was realized by close cooperation of organic, inorganic and analytical chemists, biochemists, electrochemists, experts in mass spectrometry, molecular modeling and oncology.