Book of Abstracts - Ruhr-Universität Bochum
Book of Abstracts - Ruhr-Universität Bochum Book of Abstracts - Ruhr-Universität Bochum
P-45 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors Stefan Mollin, a Jie Qin, b Ronen Marmorstein b and Eric Meggers *a a Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg, Germany. b The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA. E-mail: stefan.mollin@chemie.uni-marburg.de The design of bioactive compounds for applications in medicinal chemistry and chemical biology is focused predominantly on organic molecules, whereas inorganic compounds are mainly known for their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI). 1 However, in recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were designed as protein kinase inhibitors. 2 Here, the ability of metal complexes is used to organize organic ligands in three-dimensional space to form structures with unique and defined shapes. Based on the natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed half-sandwich complexes initially and achieved a number of potent and selective inhibitors. Phosphatidyl-inositol-3-kinases (PI3Ks) are a family of lipid kinases which act as signal transducers. They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which recruits AKT/PKB. Disruption of the PI3K signaling pathway leads to uncontrolled cell proliferation, survival, and cell growth. Thus, PI3K is a highly attractive target for the development of therapeutic agents to treat cancer and other related diseases. MARMORSTEIN and MEGGERS et al. found that a methylation of the pyridocarbazole-imide leads to a selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for PI3Ks. 3 To further increase the potency and selectivity our focus has shifted now to octahedral compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors have been synthesized with up to tenfold selectivity between the different isoforms PI3Kα and PI3Kγ. References 1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204. 2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett 2007, 8, 1177-1189. 3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E. Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316. 103
P-46 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum New Topoisomerase II Poisons Matthew P. Akerman, a Mark T. Muller, b and Orde Q. Munro* a a University of KwaZulu-Natal, School of Chemistry, AuTEK Biomed, Private Bag X01, Scottsville, Pietermaritzburg, South Africa. b University of Central Florida, College of Medicine, Biomolecular Research Annex, 12722 Research Parkway, 32826-3227, Orlando, FL, USA. E-mail: munroo@ukzn.ac.za DNA topoisomerase II (topo II) is a well-established anticancer drug target. We have identified novel metallo-drugs that act specifically on topo IIA. Topo II enzymes are essential for life and are primarily responsible for decatenation of daughter chromatids during mitosis. 1 To function as a decatenase, topo II makes a transient double strand DNA break, providing an enzyme/DNA gate through which a distal duplex strand may pass. 1 The DNA cleavage intermediate is unique since a covalent DNA-topo II complex exists during the trans-esterification at the site of the break. Compounds that react with this transient intermediate, forming a ternary DNA-enzyme-drug complex, can arrest or poison the cleavage/religation cycle, inducing permanent DNA breaks, thereby damaging the genome of the target cell. Acute cytotoxicity results as the cell accumulates double strand DNA breaks. Drugs that induce breaks are topo II poisons and are generally excellent anti-cancer agents. We have synthesized and fully characterized a series of crystalline d 8 coordination compounds with tetradentate ligands. The compounds were screened by the National Cancer Institute (NCI, USA) against their panel of 60 human cancer cell lines. The most active compound is chiral, has a mean IC50 of 14(2) �M, and is more cytotoxic than cisplatin (mean IC50 = 27 �M). Some cancer cell lines were substantially more susceptible to the new compounds than to cisplatin (ca. 12–30% of the cell lines tested, depending on the compound used). Statistical comparison of the ex vivo data for the most active compounds with drugs having known modes of action in the NCI database indicated that the cellular target is most likely topo II. This prediction was confirmed by in vitro DNA cleavage experiments using purified topo I and II and supercoiled DNA substrate. The data indicate that the compounds act as poisons at low concentrations (best current EC50 ∼ 1 �M) and as catalytic inhibitors at higher concentrations (typical EC50 ∼ 20–30 �M). The compounds are specific for topo II and do not target topo I, even at high concentrations. In vivo experiments are currently underway to assess whether the compound can target topo II in a chromatin setting. Preliminary data demonstrate that topo I is not being targeted in the cancer cell lines tested. Some of the compounds hydrolyze in aqueous buffer to generate metal-hydroxo derivatives. All hydrolysis-inert compounds bind calf thymus DNA (pH 7 phosphate buffer, 37 �C) with association constants ranging from 1.43(3) × 10 5 to 1.01(4) × 10 6 M –1 . The compounds with a high affinity for calf thymus DNA were all active cytotoxic agents in the NCI-60 screen. Reduction of the compounds by cellular levels of glutathione (pH 7 phosphate buffer, 37 �C) was followed by visible spectroscopy. Loss of the metal-to-ligand charge transfer (MLCT) band and appearance of the �–�* band of the free ligand confirmed reductive demetallation of the chelate in each case. The kinetics had second-order rate constants ranging from 0.0463(2) to 0.301(7) M –1 s –1 . Importantly, the most active compounds in the NCI-60 screen had the slowest reduction kinetics. Several structure–activity relationships for this new class of topoisomerase II poison have thus been delineated. A provisional patent has been filed and toxicology screens on the most active compounds have been scheduled. Acknowledgements: We thank AuTEK Biomed (Mintek and Harmony) for permission to publish selected data and financial support, the Department of Science and Technology (SA-COST EU Reciprocal Agreement) for a travel grant, and the Developmental Therapeutics Program (NCI, USA) cytotoxicity screens. References 1. K. C. Dong, J. M. Berger, Nature 2007, 450, 1201-1205. 104
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P-45<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors<br />
Stefan Mollin, a Jie Qin, b Ronen Marmorstein b and Eric Meggers *a<br />
a Philipps-<strong>Universität</strong> Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg,<br />
Germany. b The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA.<br />
E-mail: stefan.mollin@chemie.uni-marburg.de<br />
The design <strong>of</strong> bioactive compounds for applications in medicinal chemistry and chemical biology is<br />
focused predominantly on organic molecules, whereas inorganic compounds are mainly known for<br />
their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI). 1 However, in<br />
recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were<br />
designed as protein kinase inhibitors. 2 Here, the ability <strong>of</strong> metal complexes is used to organize organic<br />
ligands in three-dimensional space to form structures with unique and defined shapes. Based on the<br />
natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed<br />
half-sandwich complexes initially and achieved a number <strong>of</strong> potent and selective inhibitors.<br />
Phosphatidyl-inositol-3-kinases (PI3Ks) are a family <strong>of</strong> lipid kinases which act as signal transducers.<br />
They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which<br />
recruits AKT/PKB. Disruption <strong>of</strong> the PI3K signaling pathway leads to uncontrolled cell proliferation,<br />
survival, and cell growth. Thus, PI3K is a highly attractive target for the development <strong>of</strong> therapeutic<br />
agents to treat cancer and other related diseases.<br />
MARMORSTEIN and MEGGERS et al. found that a methylation <strong>of</strong> the pyridocarbazole-imide leads to a<br />
selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free<br />
imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for<br />
PI3Ks. 3 To further increase the potency and selectivity our focus has shifted now to octahedral<br />
compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors<br />
have been synthesized with up to tenfold selectivity between the different is<strong>of</strong>orms PI3Kα and PI3Kγ.<br />
References<br />
1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204.<br />
2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E.<br />
Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett<br />
2007, 8, 1177-1189.<br />
3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E.<br />
Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316.<br />
103
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