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Project 6

First Row Transition Metal Complexes with Modified Paullone and Indolo[3,2-c]quinoline Ligands

Supervisor: Prof. Vladimir Arion

Student: Michael Primik

Today metal-based drugs are of primary importance in the chemotherapeutical treatment of cancer. In almost 50% of incidences the platinum based drugs cisplatin, carboplatin and oxaliplatin are used to treat the diseases. However, severe side effects are the main disadvantages of these platinum-based anticancer-drugs.(i) Consequently we focus on other metal ions as coordination centres and molecules known to exhibit biological activity as ligands.

Indolo[3,2-d][1]benzazepines (paullones) were found to be potent inhibitors of cyclin dependent kinases (CDKs), enzymes controlling cell cycle progression.(ii)  Paullones combine the basic structures of benzazepines and indoles. A member of the group of benzazepines is the well-known tranquilizer Diazepam (Valium©), whereas the indole moiety is a basic structural component of already used anticancer drugs, e.g. vinblastine and vincristine. Especially 9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (Kenpaullone) exhibits an antiproliferative activity profile similar to that of flavopiridol, which is a well-known inhibitor of the CDK1-cyclin B complex(iii)

To overcome the poor bioavailability of the paullones coordination to metal ions has been explored.(iv)  Paullone-based complexes of ruthenium and osmium showed higher solubility in aqueous media and increased cytotoxicity.(v) However, ruthenium and osmium are not essential trace elements. Therefore, as a natural extension of the research carried out so far, the focus was turned to copper(II), a biologically more compatible metal ion, which is a co-factor essential for tumor growth an angiogenesis. High levels of copper have been found in many types of human cancers.(vi)

On top of that, the seven-membered azepine ring in paullones will be replaced by a flat six-membered pyridine ring via synthesis of indolo[3,2-c]quinolones. The effect of this replacement on antiproliferative activity, CDK inhibition, DNA intercalation, etc will be studied as well.(vi)

i) Jakupec, M.A.; Galanski, M.; Keppler, B.K. Rev. Physiol. Bioch. P. 2006, 146, 1–53.
ii) Zaharevitz, D.; Kunick, C.; Schultz, C.; Meijer, L.; Leost, M.; Gussio, R.; Senderowicz, A.; Lahusen, T.; Sausville, E. Am. Assoc. Cancer Res. 1999, Apr. 10–14.
iii) Paull, K.D.; Shoemaker, R.H.; Hodes, L.; Monks, A.; Scudiero, D.A.; Rubinstein, L.; Plowman, J.; Boyd, M.R. J. Natl. Cancer I. 1989, 81, 1088–1092.
iv) Primik, M.F.; Mühlgassner, G.; Jakupec, M.A.; Zava, O.; Dyson, P.J.; Arion, V.B.; Keppler, B.K. Inorg. Chem. 2010, 49, 302–311.
v) Filak, L.K.; Mühlgassner, G.; Jakupec, M.A.; Heffeter, P.; Berger, W.; Arion, V.B.; Keppler, B.K. J. Biol. Inorg. Chem. 2010, 15, 903–918.
vi) Gupte, A.; Humper, R.J. Cancer Treat. Rev. 2009, 35, 32–46.
vii) Lu, C.-M.; Chen, Y.-L.; Chen, H.-L.; Chen, C.-A.; Lu, P.-J.; Yang, C.-N.; Tzeng, C.-C. Bioorg. Med. Chem. 2010, 18, 1948–1957.

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