Forschung

  Arbeitsgruppe Professor Dr. Ingo Ott

Mitarbeiter: Andreas Meyer, Riccardo Rubbiani

Research

Development of New Cytostatics

Bioinorganic and Bioorganometallic Medicinal Chemistry

Mission

The general aim of our research is the development of novel innovative anticancer drugs. Within this overall interest our current projects focus mainly on the design and preparation as well as the analytical and biological evaluation of new coordination complexes.

Based on their unique geometries and reactivities metal complexes offer interactions with biological targets that can not be realised with conventional "organic" drugs. Despite this advantage "metallodrugs" are rare in practical therapy and their impact in drug development has probably been underestimated so far. However, the continuing success story of the platinum antitumor drugs (e.g. cisplatin and carboplatin) as well as the promising preclinical results of various other coordination compounds demonstrate that metal species can be valuable therapeutics.

Over the last years gold complexes have attracted major attention as novel class of anticancer metallodrugs based on the discovery of significant antiproliferative effects triggered by antirheumatic gold species such as auranofin.

The gold phosphine complex Au-Naphth depicted in the figure above represents an example for a novel antiproliferative compound developed by our group recently. Au-Naphth exhibits several features, which are highly relevant for the development of novel antitumor therapeutics. The complex effectively inhibits the proliferation of cultured tumor cells and induces apoptosis via mitochondrial pathways. These properties can be related to an interaction with the DNA and an inhibition of the enzyme thioredoxin reductase. Biodistribution studies showed that the complex is taken up into different organelles and that the naphthalimide ligand leads to an accumulation of gold in the nuclei. Furthermore, Au-Naphth significantly reduced in-vivo angiogenesis in the zebrafish model.

Methods

Besides synthetic chemistry and structural characterisation of new antitumor drugs we strongly focus on an intensive biological evaluation of the new compounds. Relevant experimental procedures include the analysis of proliferation and apoptosis, bioanalytical studies (e.g. quantification of the cellular uptake) and various enzymatic assays.

Fundings

Our projects are currently supported by DFG (Deutsche Forschungsgemeinschaft), GIF (German-Israeli-Foundation) and Volkswagenstiftung.

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 The Group

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Jobs

 At the moment all positions are filled.

 New openings will be announced on this website as soon as available.

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Publications

Journals

• Ott I., Kowalski K., Gust R., Maurer J., Mücke P., Winter R.F., Comparative biological evaluation of two ethylene linked mixed binuclear ferrocene / ruthenium organometallic species. Bioorg. Med. Chem. Lett. (2010), 20, 866-869.
• Scheffler H., You Y., Ott I.*, Cytotoxicity, cellular and nuclear uptake of a series of chloro gold(I) phosphine complexes. Polyhedron (2010), 29, 66-69.
• Bagowski C. P., You Y., Scheffler H., Vlecken D.H., Schmitz D. J., Ott I.*, Naphthalimide gold(I) phosphine complexes as anticancer metallodrugs. Dalton Trans. (2009), 10799-10805.
• Bieda R., Ott I., Gust R., Sheldrick W.S.,Cytotoxic rhodium(III) polypyridyl complexes containing the tris(pyrazolyl)methane coligand: synthesis, DNA-binding properties and structure-activity relationships., Eur. J. Inorg. Chem. (2009), 25, 3821-3831.
• Patra M., Gasser G., Pinto A., Merz K., Ott I., Bandow E. J., Metzler-Nolte N., Synthesis and biological evaluation of chromium bioorganometallics based on the antibotic platensimycin lead structure. ChemMedChem (2009), 4, 1930-1938.
• Nazif A., Bangert J. A., Ott I., Gust R., Stoll R., Sheldrick W. S., Dinuclear organoiridium(III) mono- and bis-intercalators with rigid bridging ligands: synthesis, cytotoxicity and DNA-binding. J. Inorg. Biochem. (2009), 103, 1405-1414.
• Walther C., Ott I., Gust R., Neundorf I., Specific labeling with potent radionuclides alters the uptake of cell-penetrating peptides, Biopolymers (2009), 92, 445-451.
• Kappert K., Tsuprykov O., Kaufmann J., Fritzsche J., Ott I., Goebel M., Bahr I. N., Hassle P. L., Gust R., Fleck E., Unger T., Stawowy P., Kintscher U., Chronic treatment with losartan results in sufficient serum levels of the metabolite EXP3179 for PPARgamma activation. Hypertension (2009), 54, 738-743.
• Butsch K., Elmas S., Gupta N. S., Gust R., Heinrich F., Klein A., von Mering Y., Neugebauer M., Ott I., Schäfer M., Scherer H., Schurr T., Organoplatinum(II) and -palladium(II) complexes of nucleobases and their derivatives. Organometallics (2009), 28, 3906-3915.
• Hille A., Ott I., Kitanovic A., Kitanovic I., Alborzinia H., Lederer E., Wölfl S., Metzler-Nolte N., Schäfer S., Sheldrick W.S., Bischof C., Schatzschneider U., Gust R., [N, N'-Bis(salicylidene)-1,2-phenylenediamine] metal complexes with cell death promoting properties. J. Biol. Inorg. Chem. (2009), 14, 711-725.
• Bieda R., Ott I., Dobroschke M., Prokop A., Gust R., Sheldrick W. S., Structure-activity relationships and DNA binding properties of apoptosis inducing rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS₃. J. Inorg. Biochem. (2009), 103, 698-708.
• N'Dongo H. W. P., Ott I., Gust R.,Schatzschneider U., Microwave-assisted solid-phase synthesis, cellular uptake, and cytotoxicity studies of cymantrene-peptide bioconjugates. J. Organomet. Chem. (2009), 694, 823-827.
• Ott I.*, Qian X., Xu Y., Vlecken D. H., Marques I. J., Kubat D., Will J., Sheldrick W. S., Jesse P., Prokop A., Bagowski C. P., A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor. J. Med. Chem. (2009), 53, 763-770.
• Ott I.*, Kircher B., Bagowski C. P., Vlecken D. H. W., Ott E. B., Will J., Bensdorf K., Sheldrick W. S., Gust R., Modulation of the biological properties of aspirin by bioorganometallic derivatisation. Angew. Chem. Int. Ed. (2009), 48, 1160-1163.
• Sinning C., B. Watzer, Coste O., Nüsing R. M., Ott I., Ligresti A., Di Marzo V., Imming P., New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide. J. Med. Chem. (2008), 51, 7800-7805.
• Schlenk M., Ott, Gust R., Cobalt-alkyne complexes with imidazoline ligands as estrogenic carriers. J. Med. Chem. (2008), 51, 7318-7322.
• Ott I.*, Xu Y., Liu J., Kokoschka M., Harlos M., Sheldrick W.S., Qian X., Sulfur substituted naphthalimides as photoactivatable anticancer agents: DNA interaction, fluorescence imaging and phototoxic effects in cultured tumor cells. Bioorg. Med. Chem. (2008), 16, 1707-1716.
• Schatzschneider U., Niesel J., Ott I., Gust R., Alborzinia H., Wölfl S., Cellular uptake, cytotoxicity and metabolic profiling, of human cancer cells treated with ruthenium(II) polypyridyl complexes. ChemMedChem (2008), 3, 1104-1109.
• Scharwitz M. A., Ott I., Gust R., Kromm A., Sheldrick W.S., Synthesis, cellular uptake and structure-activity relationships for potent cytotoxic trichlorididoiridium(III) polypyridyl complexes. J. Inorg. Biochem. (2008), 102, 1623.
• Harlos M., Ott I., Gust R., Alborzinia H., Wölfl S., Kromm A., Sheldrick W. S., Synthesis, biological activity and structure activity relationships for potent cytotoxic rhodium (III) polypyridyl complexes. J. Med. Chem. (2008), 51, 3924-3933.
• Ott I.*, Scharwitz M., Scheffler H., Sheldrick W. S., Gust R., Atomic absorption spectrometric determination of the iridium content of tumor cells exposed to an iridium metallodrug. J. Pharm. Biomed. Anal. (2008), 47, 938-942.
• Kirin S. I., Ott I, Gust R., Mier W., Weyhermüller T., Metzler-Nolte N., Cellular uptake quantification of metallated peptide and peptide nucleic acid bioconjugates by atomic absorption spectroscopy. Angew. Chem., Int. Ed. (2008), 47, 955-959.
• Niesel J., Pinto A., Peindy N`Dongo H. W., Merz K., Ott I., Gust R., Schatzschneider U. Photoinduced CO-release, cellular uptake and cytotoxicity of a tris(pyrazolyl)methane (tpm) manganese tricarbonyl complex. Chem. Commun. (2008), 1798-1800.
• Sergeant C. D., Ott I.*, Sniady A., Meneni, S., Gust R., Rheingold A. L., Dembinski R., Metallo-nucleosides: synthesis and biological evaluation of hexacarbonyl dicobalt 5-alkynyl-2'-deoxyuridines. Org. Biomol. Chem. (2008), 6, 73-80.
• Kapp T., Krüger M., Ott I., Steiner S., Schumacher P., Nachbaur D., Gastl G., Gust R., Kircher B., Biological effect of mono- and dinuclear alkylamine platinum(II) compounds on human lymphoma cells. J. Inorg. Biochem. (2008), 102, 713-720.
• Scharwitz M. A., Ott I., Geldmacher Y., Gust R., Sheldrick W.S. "Cytotoxic half-sandwich rhodium(III) complexes: polypyridyl ligand influence on their DNA binding properties and cellular uptake." J. Organomet. Chem. (2008), 693, 2299-2309.
• Schäfer S., Ott I., Gust R., Sheldrick W. S., Influence of the polypyridyl (pp) ligand size on the DNA binding properties, cytotoxicity and cellular uptake of organoruthenium(II) complexes of the types [(η⁶-C₆Me₆)Ru(L)(pp)]ⁿ⁺ (L=Cl, n=1; L= (NH₂)₂CS, n=2). Eur. J. Inorg. Chem. (2007), 3034-3046.
• Ott I.*, Scheffler H., Gust R., Development of a method for the quantification of the molar gold concentration in tumor cells exposed to gold containing drugs. ChemMedChem (2007), 2, 702-707.
• Meneni S., Ott I., Sergeant C.D., Sniady A., Gust R., Dembinski R., 5-Alkynyl-2-deoxyuridines: chromatography-free synthesis and cytotoxicity evaluation against human breast cancer. Bioorg. Med. Chem. (2007), 15, 3082-3088.
• Banekovich C., Ott I.*, Koch T., Matuszczak B., Gust R., Synthesis and biological activities of novel dexibuprofen tetraacetylriboflavin conjugates. Bioorg. Med. Chem. Lett. (2007), 17, 683-687.
• Ott I.*, Abraham A., Schumacher P., Shorafa H., Gastl G., Gust R., Kircher B., Synergistic and additive antiproliferative effects on human leukemia cell lines induced by combining acetylenehexacarbonyldicobalt complexes with the tyrosine kinase inhibitor imatinib. J. Inorg. Biochem. (2006), 100, 1903-1906.
• Ott I., Kircher B., Schumacher P., Schmidt K., Gust R., Antitumoractive cobalt-alkyne complexes derived from acetylsalicylic acid: studies on the mode of drug action., J. Med. Chem. (2005), 48, 622-629.
• Wiglenda T., Ott I., Kircher B., Schumacher P., Schuster D., Langer T., Gust R., Synthesis and pharmacological evaluation of 1H-imidazoles as ligands for the estrogen receptor and cytotoxic inhibitors of the cyclooxygenase. J. Med. Chem. (2005), 48, 6516-6521.
• Ott I., Koch T., Shorafa H., Bai Z., Pöckel D., Steinhilber D., Gust R. Synthesis, cytotoxicity, cellular uptake and influence on eicosanoid metabolism of cobalt-alkyne modified fructoses in comparison to auranofin and the cytotoxic COX inhibitor Co-ASS. Org. Biomol. Chem. (2005), 3, 2282-2286.
• Ott I., Gust R., Stability, protein binding and thiol interaction studies on [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt., Biometals (2005), 18, 171-177.
• Gust R., Ott I., Posselt D., Sommer K., Development of cobalt(3,4-diarylsalen)complexes as tumor therapeutics., J. Med. Chem. (2004), 47, 5837-5846.
• Ott I., Kircher B., Heinisch G., Matuszczak B., Substituted pyridazino[3,4-b][1,5]benzoxazepin-5(6H)ones as multidrug resistance modulating agents., J. Med. Chem. (2004), 47, 4627-4630.
• Ott I., Kircher B., Gust R., Investigations on the effects of cobalt-alkyne complexes on leukemia and lymphoma cells: cytotoxicity and cellular uptake., J. Inorg. Biochem. (2004), 98, 485-489.
• Amann A., Decristoforo C., Ott I., Wenger M., Bader D., Alberto R., Putz G., Surfactant protein B labelled with [^99mTc(CO)₃(H₂O)₃]⁺ retains biological activity in vitro., Nucl. Med. Biol. (2001), 28, 243-250.

Reviews and other contributions in journals

• Ott I.*, Metalle: Bausteine für Wirkstoffe. Nachrichten aus der Chemie (2009), 57, 628-631.
• Ott I.*, On the medicinal chemistry of gold complexes as anticancer drugs. Coord. Chem. Rev. (2009), 253, 1670-1681.
• Ott I.*, Kircher B., Dembinski R., Gust R. Alkyne hexacarbonyl dicobalt complexes in medicinal chemistry and drug development. Expert Opin. Therap. Patents (2008), 18, 327-337.
• Ott I.*, Gust R., Organometallverbindungen: Hilfreich in der Therapie von Tumorerkrankungen. Pharmazeutische Zeitung (2007), 32, 74-76.
• Ott I.*, Gust R., Non platinum metal complexes as anti-cancer agents. Arch. Pharm. Chem. Life Sci. (2007), 340, 117-126.
• Ott I., Gust R., Preclinical and clinical studies on the use of platinum complexes for breast cancer treatment. Anti-Cancer Agents in Medicinal Chemistry (2007), 7, 95-110.
• Ott I., Gust R., Medizinische Chemie der Platinkomplexe. Pharm. Unserer Zeit (2006), 35, 124-133.

 Patents

• Gust R., Ott I., Sheldrick W. S., Harlos M. Octahedral metal(III) polypyridyl complexes and their use in prevention and treatment of cancer. EP2072521 (A1), WO2009080482 (A1)

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