Publikationen

Ausgewählte Publikationen 1990-2014


B. Clement* und T. Kunze, Hepatic microsomal N-hydroxylation of adenine to 6-N-hydroxylamino-purine, Biochemical Pharmacology 39, 925-933 (1990).

B. Clement*, M. Immel, H. Pfundner, S. Schmitt und M. Zimmermann, New aspects of the microsomal N-hydroxylation of benzamidines, in N-oxidation of drugs: Biochemistry, pharmacology and toxicology, ed. by P. Hlavica and L.A. Damani, 185-204, London, Chapman and Hall, 1991.

B. Clement*, M. Immel, R. Terlinden und F.J. Wingen, Reduction of amidoxime derivatives to pentamidine in vivo, Archiv der Pharmazie 325, 61-62 (1992).

B. Clement* und T. Kunze, The reduction of 6-N-hydroxylaminopurine to adenine by xanthineoxidase, Biochemical Pharmacology 44, 1501-1509 (1992).

B. Clement* und T. Kunze, The in vitro oxygenation of N,N'-diphenylguanidines, Xenobiotica 23, 155-167 (1993).

B. Clement*, F. Jung und H. Pfundner, N-hydroxylation of benzamidine to benzamidoxime by a reconstituted cytochrome P-450 oxidase system from rabbit liver: Involvement of P-450 IIC3, Molecular Pharmacology 43, 335- 342 (1993).

B. Clement*, M.H. Schultze-Mosgau und H. Wohlers, Cytochrome P-450 dependent N-hydroxylations of a guanidine (debrisoquine), microsomal catalyzed reduction and further oxidation of the N-hydroxyguanidine metabolite to the urea derivative: similarity with the oxidation of arginine to citrulline and NO, Biochemical Pharmacology 46, 2249-2267 (1993).

B. Clement*, M.H. Schultze-Mosgau, P.H. Richter und A. Besch, Cytochrome P 450 dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) and microsomal retroreduction of the N-hydroxylated product, Xenobiotica 24, 671-688 (1994).

B. Clement* und F. Jung, N-Hydroxylation of the antiprotozoal drug pentamidine catalysed by rabbit liver cytochrome P-450 2C3 or by human liver microsomes, microsomal retroreduction and further oxidative transformation of the formed amidoximes, possible relationship to the biological oxidation of arginine to NG-hydroxyarginine, citrulline and nitric oxide, Drug Metabolism and Disposition 22, 486-497 (1994).

B. Clement*, E. Schnörwangen, T. Kämpchen, P. Mordvintcev und A. Mülsch, Synthesis of 15N-Hydroxy-L-arginine and ESR and 15N NMR studies for the elucidation of the molecular mechanism of enzymic nitric oxide formation from L-arginine, Archiv der Pharmazie 327, 793-798 (1994).

B. Clement* und C. Mladek, Biotransformations-untersuchungen im Hühnerei, Teil 1: Metabolische Umwandlungen von 7-Ethoxycumarin, Pharmazie 50, 207-210 (1995).

B. Clement* und F. Jung, N-hydroxylation and N-dealkylation by P450 2C3 of N-methylbenzamidine: N-oxygenation and N-oxidative dealkylation of one functional group, Xenobiotica 25, 443-455 (1995)

A. Mülsch, P. Mordvintcev, E. Bassenge, F. Jung, B. Clement und R. Busse, In vivo spin trapping of glycerol trinitrate derived NO in blood vessels and organs, Circulation 92, 1876-1882 (1995).

D. Mansuy, J.L. Boucher und B. Clement, On the mechanism of nitric oxide formation upon oxidative cleavage of C=N(OH) bonds by NO-synthases and cytochromes P450, Biochimie 77, 661-667 (1995)

B. Clement*, M. Weide und D. Ziegler, Inhibition of purified and membrane-bound flavin containing monooxygenase 1 by N,N-dimethylaminostilbene carboxylates, Chemical Research in Toxicology 9, 599-604 (1996)

B. Clement*, M. Demesmaeker und S. Linne, Microsomal catalyzed N-hydroxylation of guanabenz and reduction of the N-hydroxylated metabolite: Characterization of the two reactions and genotoxic potential of guanoxabenz, Chemical Research in Toxicology 9, 682-688 (1996)

B. Clement*, W. Möller und R. Lomb, Isolation and characterization of the protein components of the liver microsomal O2 insensitive NADH-benzamidoxime reductase, Journal of Biological Chemistry 272, 19615-19620, (1997)

B. Clement* und M. Demesmaeker, Formation of guanoxabenz from guanabenz in human liver; a new metabolic marker for CYP1A2, Drug Metabolism and Disposition 25, 1266-1271 (1997)

B. Clement* und M. Demesmaeker, Microsomal catalyzed N-hydroxylation of guanfacine and reduction of N-hydroxyguanfacine, Archiv der Pharmazie 330, 303-306 (1997)

B. Clement*, Oxidation and reduction of nitrogen via C4P450: Importance of the reduction of genotoxic N-hydroxylated functional groups, in Drug Metabolism: Towards the next millenium, ed. by N.J. Goodruham, 59-71, Amsterdam, IUS Press, (1998).

A. Jousserandot, J. L. Boucher, Y. Henry, B. Niklaus, B. Clement and D. Mansuy, Microsomal cytochrome P450-dependent oxidation of N-hydroxy-guanidines, amidoximes and ketoximes: Mechanism of the oxidative cleavage of their C=N (OH) bonds with formation of nitrogen oxides. Biochemistry 37, 17179-17191 (1998).

B. Clement*, J. L. Boucher, D. Mansuy and A. Harsdorf, Microsomal formation of nitric oxide and cyanamides form non-physiological N-hydroxyguanidines: N-Hydroxydebriosoquine as a model substrate. Biochemical Pharmacology 58, 439-445 (1999).

M. Feelisch, P. Kotsonis, J. Siebe, B. Clement und H. H. H. W. Schmidt, The soluble guanylyl cyclase inhibitor, ODQ, is a non slective heme protein inhibitor of NO synthase and other cytochrome P450 enzymes involved in NO donor bioactivation. Molecular Pharmacology 56, 243-253 (1999).

B. Clement* und U. Girreser, Characterization of biguanides by 15N-NMR spectroscopy. Magnetic Resonance in Chemistry 37, 662-666 (1999).

B. Clement*, D. Behrens, W. Möller und J. R. Cashman, Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime-reductase and human liver microsomes, Chemical Research in Toxicology 13, 1037-1045 (2000).

C. R. Ganellin, L. A. Mitscher, B. Clement, T.-H. Kobayashi, E. Kyburz, A. Marcinal, A. Munge, G. Tarzia, J. Topliss, University education of medicinal chemists: comparison of eight countries. European Journal of Medicinal Chemistry 35, 163-174 (2000).

B. Clement*, K. Christiansen und U. Girreser, Phase 2 Metabolites of N-Hydroxylated Amidines (Amidoximes): Synthesis, in vitro Formation by Pig Hepatocytes, and Mutagenicity Testing, Chemical Research in Toxicology 14, 319-326 (2001).

U. Girreser, M.König und B. Clement, Characterization of para-substituted benzamidoximes and benzamidinium salts by 15N NMR Spectroscopy. Magnetic Resonance in Chemistry 40, 202-206 (2002).

B. Clement*, Reduction of N-Hydroxylated Compounds: Amidoximes (N-Hydroxyamidines) as prodrugs of amidines, Drug Metabolism Reviews 34, 565-579 (2002).

B. Clement* und K. Lopian, Characterization of the in vitro biotransformation of the new, orally active, direct thrombin inhibitor Ximelagatran, an amidoxime and ester prodrug, Drug Metabolism and Disposition 31, 645-661 (2003).

P. Ettmayer, G. Amidon, B. Clement and B. Testa, Lessons learned from marketed and investigational prodrugs. Journal of Medicinal Chemistry 47, 2393-2404 (2004). (2. Platz im Ranking aller J. Med. Chem.- Artikel des Jahres 2004; siehe http://www.acsmedchem.org/)

Alle Publikationen ab 2005 (ohne abstracts)


B. Clement*, M. Weide, U. Wolschendorf, I. Kock
Eine zweistufige Synthese von cytostatisch wirksamen Benzo[c]phenanthridin-Derivaten.
Angewandte Chemie, 2005, 117, 641-645
Engl. Version: A two-step synthesis of cytostatically active benzo[c]phenanthridine derivatives.
Angewandte Chemie International Edition 2005, 44, 635-638

A. K. Fröhlich, U. Girreser, B. Clement*
Metabolism of N-hydroxyguanidines (N-hydroxydebrisoquine) in human and porcine hepatocytes: reduction and formation of glucuronides
Drug Metabolism & Disposition, 2005, 33, 1532-1537

A.K. Fröhlich, U. Girreser and B. Clement*
Metabolism of benzamidoxime (N-hydroxyamidine) in human hepatocytes and role of UDP-glucuronosyltransferases.
Xenobiotica, 2005, 35, 17-25

I. Kock, D. Heber, M. Weide, U. Wolschendorf, B. Clement*
Synthesis and biological evaluation of 11-substituted 6-aminobenzo[c]phenanthridine derivatives, a new class of antitumor agents.
Journal of Medicinal Chemistry, 2005, 48, 2772-2777

I. Kock, B. Clement*
A new synthetic approach to the benzo[c]phenanthridine ring system.
Synthesis, 2005, 7, 1052-1054

B. Clement*, D. Behrens, J. Amschler, K. Matschke, S. Wolf, A. Havemeyer
Reduction of sulfamethoxazole and dapsone hydroxylamines by a microsomal enzyme system purified from pig liver and human liver microsomes.
Life Sciences, 2005, 77, 205-219

B. Clement*, S. Mau, S. Deters, A. Havemeyer
Hepatic, extrahepatic, microsomal, and mitochondrial activation of the N-hydroxylated prodrugs benzamidoxime, guanoxabenz, and Ro 48-3656.
Drug Metabolism & Disposition, 2005, 33, 1740-1747

S. Heberling, U. Girreser, S. Wolf, B. Clement*
Oxygen-insensitive enzymatic reduction of oximes to imines.
Biochemical Pharmacology, 2006, 71, 354-356

I. Zebothsen, T. Kunze, B. Clement*
Inhibitory effects of cytostatically active 6-aminobenzo[c]phenanthridines on cytochrome P450 enzymes in human hepatic microsomes.
Pharmacology & Toxicology, 2006, 99, 37-43

I. Zebothsen, U. Girreser, B. Clement*
Metabolism of cytostatically active 6-aminobenzo[c]phenanthridines by human and porcine hepatic microsomes and recombinant cytochrome P450 enzymes.
Xenobiotica, 2006, 36, 581-595

B. Clement*, T. Kunze, S. Heberling
Reduction of Nω-hydroxy-L-arginine to L-arginine by pig liver microsomes, mitochondria, and human liver microsomes.
Biochemical and Biophysical Research Communications, 2006, 349, 869-873

A. Havemeyer, F. Bittner, S. Wollers, R. Mendel, T. Kunze, B. Clement*
Identification of the missing component in the mitochondrial benzamidoxime prodrug converting system as a novel molybdemum enzyme.
Journal of Biological Chemistry, 2006, 281, 34796-34802

B. Clement*, A. Bürenheide, W. Rieckert, J. Schwarz
Diacetyldiamidoximester of pentamidine, a prodrug for treatment of protozoal diseases: Synthesis, in vitro and in vivo biotransformation.
ChemMedChem, 2006, 1, 1260-1267

J.A. Hutchinson, P. Riquelme, J. Wundt, J.G. Hengstler, F. Fändrich, B. Clement, H. Ungefroren*
Could treatment with neohepatocytes benefit patients with decompensated chronic liver disease.
American Journal of Hematology, 2007, 82, 947-948 (und Erratum vom 05.10.2007)

A. Stürzebecher, D. Dönnecke, A. Schweinitz, O. Schuster, P. Steinmetzer, U. Stürzebecher, J. Kotthaus, B. Clement, J. Stürzebecher, T. Steinmetzer*
Highly potent and selective substrate analogue factor Xa inhibitors containing D-homophenylalanine analogues as P3 residue: part 2.
ChemMedChem, 2007, 2, 1043-1053

C. Reeh, J. Wundt, B. Clement*
N,N-Dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines.
Journal of Medicinal Chemistry, 2007, 50, 6730-6734

D. Schade, K. Töpker-Lehmann, J. Kotthaus, B. Clement*
Synthetic approaches to Nδ-methylated L-arginine, Nω-hydroxy-L-arginine, L-citrulline, and Nδ-cyano-L-ornithine.
Journal of Organic Chemistry, 2008, 73, 1025-1030

J. Kotthaus, D. Schade, K. Töpker-Lehmann, E. Beitz, B. Clement*
Nδ-methylated L-arginine derivatives and their effects on the nitric oxide generating system.
Bioorganic & Medicinal Chemistry, 2008, 16, 2305-2312

A. Bürenheide, T. Kunze, B. Clement*
Inhibitory effects on cytochrome P450 enzymes of pentamidine and its amidoxime pro-drug.
Basic & Clinical Pharmacology & Toxicology, 2008, 103, 61-65

D. Schade, J. Kotthaus, B. Clement*
Efficient synthesis of optically pure Nω-alkylated L-arginines.
Synthesis, 2008, 15, 2391-2397

R. Reh, J. Ozols, B. Clement*
Involvement of Stearyl-CoA-Desaturase (SCN) in the reduction of amidoxime prodrugs.
Xenobiotica, 2008, 38, 1177-1190

S. Grünewald, B. Wahl, F. Bittner, H. Hungeling, S. Kanzow, J. Kotthaus, U. Schwering, R.R. Mendel, B. Clement*
The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.
Journal of Medicinal Chemistry, 2008, 51, 8173-8177

J. Kotthaus, D. Schade, N. Muschick, E. Beitz, B. Clement*
Structure-activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads.
Bioorganic and Medicinal Chemistry, 2008, 16, 10205-10209

P. Riquelme, J. Wundt, M. Brulport, J.Yu, A. Sotnikova, U. Girreser, F. Braun, B. Soria, H. Ungefroren, A. Nüssler, F. Fändrich, B. Clement, J.G. Hengstler, J. A. Hutchinson*
A refined characterisation of the neohepatocyte phenotype necessitates a reappraisal of the transdifferentiation hypothesis.
Differentiation, 2009, 77, 263-276

M. Rostami-Yazdi*, B. Clement, T.J. Schmidt, D. Schinor, U. Mrowietz
Detection of fumaric acid esters in human urine: implications for their mode of action.
Journal of Investigative Dermatology, 2009, 129, 231-234

U. Bluhm, J.L. Boucher, U. Buss, B. Clement*, F. Friedrich, U. Girreser, D. Heber, T. Lam, M. Lepoivre, M. Rostaie-Gerylow, U. Wolschendorf
Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases.
European Journal of Medicinal Chemistry, 2009, 44, 2877-2887

A. Schweinitz, D. Dönnecke, A. Ludwig, P. Steinmetzer, A. Schulze, J. Kotthaus, S. Wein, B. Clement, T. Steinmetzer*
Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors.
Bioorganic and Medicinal Chemistry Letters, 2009, 19, 1960-965

D. Schade, J. Kotthaus, H. Hungeling, J. Kotthaus, B. Clement*
The peptidylglycine alpha-amidating monooxygenase (PAM): a novel prodrug strategy for amidoximes and N-hydroxyguanidines?
ChemMedChem, 2009, 4, 1595-1599

A. Schröder, J. Kotthaus, D. Schade, B. Clement, K. Rehse*
Arylazoamidoximes and related compounds as NO-modulators.
Archiv der Pharmazie, 2010, 343, 9-16

J. Kotthaus, T. Steinmetzer, J. Kotthaus, D. Schade, A. van de Locht, B. Clement*
Metabolism and distribution of two highly potent and selective peptidomimetic inhibitors of matriptase.
Xenobiotica, 2010, 40, 93-101

D. Schade*, J. Kotthaus, B. Clement
Modulating the NO generating system from a medicinal chemistry perspective: Current trends and therapeutic options in cardiovascular disease.
Pharmacology & Therapeutics, 2010, 126, 279-300

M. Rostami-Yazdi, B. Clement, U. Mrowietz
Pharmacokinetics of anti-psoriatic fumaric acid esters in psoriasis patients.
Archives of Dermatological Research, 2010, 302, 531-38

B. Wahl, D. Reichmann, D. Niks, N. Krompholz, A. Havemeyer, B. Clement, T. Messerschmidt, M. Rothkegel, H. Biester, R. Hille, R. Mendel, F. Bittner
Biochemical and spectroscopic characterization of the human mitochondrial amidoxime reducing components hmARC-1 and hmARC-2 suggests the existence of a new molybdenum enzyme family in eukaryotes.
Journal of Biological Chemistry, 2010, 285, 37847-59

J. Kotthaus, B. Wahl, A. Havemeyer, J. Kotthaus, D. Schade, D. Garbe-Schönberg, R. Mendel, F. Bittner, B. Clement*
Reduction of Nω-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC).
Biochemical Journal, 2010, 433, 383-391

A. Havemeyer, S. Grünewald, B. Wahl, F. Bittner, R. Mendel, P. Erdélyi, J. Fischer, B. Clement
Reduction of N-hydroxy-sulfonamides, including N-hydroxy-valdecoxib, by the molybdenum-containing enzyme mARC.
Drug Metabolism & Disposition, 2010, 38, 1917-21

A. Havemeyer, J. Lang, B. Clement*
The fourth mammalian molybdenum enzyme mARC: Current state of research.
Drug Metabolism Reviews, 2011, 43, 524-539

J. Kotthaus, H. Hungeling, C. Reeh, J. Kotthaus, D. Schade, S. Wein, S. Wolffram, B. Clement*, Synthesis and biological evaluation of L-valine-amidoximeesters as double prodrugs of amidines.
Bioorganic and Medicinal Chemistry, 2011, 19, 1907-1914

J. Kotthaus, J. Kotthaus, D. Schade, U. Schwering, H. Hungeling, H. Müller-Fielitz, W. Raasch, B. Clement*
New prodrugs of the antiprotozoal drug pentamidine.
ChemMedChem, 2011, 6, 2233-2242

J. Kotthaus, T. Steinmetzer, A. van de Locht, B. Clement*
Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes).
Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, 26, 115-122

D. Schade*, J. Kotthaus, N. Klein, J. Kotthaus, B. Clement*
Prodrug design for the potent cardiovascular agent Nω-hydroxy-L-arginine (NOHA): Synthetic approaches and physicochemical characterization.
Organic Biomolecular Chemistry, 2011, 9, 5249-5259

K.S. Altmann, A. Havemeyer, E. Beitz, B. Clement*
Dimethylarginine-dimethylaminohydrolase-2 (DDAH-2) does not metabolize methylarginines.
ChemBioChem, 2012, 13, 2599-2604

J. Kotthaus, D. Schade, J. Kotthaus, B. Clement*
Designing modulators of dimethylarginine dimethylaminohydrolase (DDAH) – A focus on selectivity over arginase.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, 27, 24-28

N. Krompholz, C. Krischkowski, D. Reichmann, D. Garbe-Schönberg, R.-R. Mendel, F. Bittner, B. Clement*, A. Havemeyer
The mitochondrial amidoxime reducing component (mARC) is involved in detoxification of N-hydroxylated base analogues.
Chemical Research in Toxicology, 2012, 25, 2443-2450

C.Meier, J. Kotthaus, L. Stenzel, U. Girreser, D. Heber, B. Clement*
Synthesis and physicochemical characterization of novel 6-aminopyrido[3,4-c][1,9]phenanthrolines as aza-analogs of benzo[c]phenanthridines.
Tetrahedron, 2012, 68, 9105-9112

S. Dibbert, B. Clement, T. Skak-Nielsen, U. Mrowietz, M. Rostami-Yazdi
Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism.
Archives of Dermatological Research, 2013, 305, 447-451

D. Froriep, B. Clement*, F. Bittner, R.R. Mendel, D. Reichmann, W. Schmalix, A. Havemeyer
Activation of the anti-cancer agent upamostat by the mARC enzyme systeme.
Xenobiotica, 2013, 43, 780-784

U. Girreser*, U. Bluhm, B. Clement, D. Heber
1H, 13C and 15N NMR spectral analysis of substituted 1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidines.
Magnetic Resonance in Chemistry, 2013, 51, 714-721

T.M. Lakowski*, A. Szeitz, M.L. Pak, D. Thomas, M.I. Vhuiyan, J. Kotthaus, B. Clement, A. Frankel
MS fragmentation patterns of momoethylarginine species and the quantification of all methylarginine species in yeast using MRM.
Journal of Proteomics, 2013, 80, 43-54

C. Meier, P. Sömmer, U. Girreser, B. Clement*
Synthesis of pyrido[3,4-c][1,9]phenanthroline - a five-step procedure to a novel N-containing ring skeleton.
Synthesis, 2013, 45, 893-895

B. Plitzko, G. Ott, D. Reichmann, C.J. Henderson, C.R. Wolf, R. Mendel, F. Bittner, B. Clement*, A. Havemeyer
The involvement of mitochondrial amidoxime reducing components 1 and 2 and mitochondrial cytochrome b5 in N-reductive metabolism in human cells.
Journal of Biological Chemistry, 2013, 288, 20228-20237

U. Bluhm, J.-L. Boucher, B. Clement, U. Girreser, D. Heber, B. Ramassamy, U. Wolschendorf
Synthesis, characterization and NO synthase inhibition testing of 2-aryl-5-aroyl-3,4,5,6-tetrahydropyrimidinium chlorides.
Journal of Heterocyclic Chemistry, 2014, doi: 10.1002/jhet.1925

H. H. Jakobs, D. Froriep, A. Havemeyer, R. R. Mendel, F. Bittner, B. Clement*
The mitochondrial amidoxime reducing component (mARC): Involvement in metabolic reduction of N-oxides, oximes and N-hydroxyamidinohydrazones.
ChemMedChem, 2014, 9, 2381-2387, doi: 10.1002/cmdc.201402127

H. H. Jakobs, M. Mikula, A. Havemeyer, A. Strzalkowska, M. Borowa Chmielak, A. Dzwonek, M. Gajewska, E. E. Hennig, J. Ostrowski, B. Clement*
The N-reductive system composed of mitochondrial amidoxime reducing component (mARC), cytochrome b5 (CYB5B) and cytochrome b5 reductase (CYB5R) is regulated by fasting and high fat diet in mice.
PLoS One, 2014, 9 (8), e105371, doi: 10.1371/journal.pone.0105371

G. Ott, D. Reichmann, C. Börger, I. Cascorbi, F. Bittner, R. Mendel, T. Kunze, B. Clement*, A. Havemeyer
Functional characterization of protein variants encoded by nonsynonymous single nucleotide polymorphisms in mARC1 and mARC2 in healthy caucasians.
Drug Metabolism & Disposition, 2014, 42, 718-725

G. Ott, A. Havemeyer, B. Clement*
The mammalian molybdenum enzymes of mARC.
Journal of Biological Inorganic Chemistry, 2014, doi: 10.1007/s00775-014-1216-4

G. Ott, B. Plitzko, C. Krischkowski, D. Reichmann, F. Bittner, R.R. Mendel, T. Kunze, B Clement, A. Havemeyer
Reduction of sulfamethoxazole hydroxylamine (SMX-HA) by the mitochondrial amidoxime reducing component (mARC).
Chemical Research in Toxicology Toxicol. 2014, 27, 1687-1695, doi: 10.1021/tx500174u

D. Schade*, J. Kotthaus, L. Riebling, J. Kotthaus, H. Müller-Fielitz, W. Raasch, O. Koch, N. Seidel, M. Schmidtke, B. Clement
Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
Journal of Medical Chemistry, 2014, 57, 759-769

L. Schwarz, U. Girreser, B. Clement*
Synthesis and characterization of para-substituted N,N′-dihydroxybenzamidines and their derivatives as model compounds for a class of prodrugs.
European Journal of Organic Chemistry, 2014, 9, 1961-1975

L. Schwarz, U. Girreser, B. Clement*
Synthesis of p-amino-N,N′-dihydroxybenzamidine using a TBDMS protecting group protocol.
Tetrahedron Letters, 2014, 55, 3322-3324

E. Bauch, D. Reichmann, R.R. Mendel, F. Bittner, A.M. Manke, P. Kurz, U. Girreser, A. Havemeyer, B. Clement*
Electrochemical and mARC-catalyzed enzymatic reduction of para-substituted benzamidoximes: consequences for the prodrug concept "amidoximes instead of amidines".
ChemMedChem, 2014, doi: 10.1002/cmdc.201402437

B. Cohrs, Y. Zhao, U. Lützen, J. Culman, B. Clement, M. Zuhayra
In vivo SPECT imaging of [123l]-labeled pentamidine prodrugs for the treatment of human African trypanosomaisis, pharmakokinetics und bioavailability studies in rats International Journal of Pharmaceutics 477, 167-175, 2014, DOI: 10.1016/j.ijpharm.2014.10
B. Plitzko, A. Havemeyer, T. Kunze, B. Clement*
The pivotal role of the mitochondrial amidoxime reducing component 2 in protecting human cells againt apoptotic effects of the base analog N6-hydroxylaminopurine
The Journal of Biological Chemistry, 290, 2015, 10126-10135, DOI: 10.1074/jbc.M115.640052

T. Steinhauer, D. Längle, C. Meier, U. Girreser, L. Stenzel, D. Heber, B. Clement*
Triggering the Directional Selectivity of a Ring-Closure Reaction Leads to Pyridoazacarbazoles with Anticancer Properties
Chemistry a European journal , 2015, 21, 6668-6672, DOI: 10.1002/chem201500156

D. Schade, J. Kotthaus, L. Riebling, J. Kotthaus, H. Müller-Fielitz, W. Raasch, A: Hoffmann, M. Schmidtke, B. Clement*
Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailibility
Journal of Pharmaceutical Sciences, 2015, 104, 3208-3219, DOI: 10.1002/jps.24508

B. Testa, B. Clement
Biotranformation Reactions and their Enzymes
The Practice of Medicinal Chemistry, 4th edition, 2015, 561-584, DOI: 10.1016/B978-0-12-417205-0.00024-9

T. Lakowski*, M. Pak, A. Szeitz, D. Thomas, M. Vhuiyan, B. Clement, A. Frankel
Arginine methylation in yeast proteins during stationary-phase growth and heat shock
Amino Acids, 2015, 47, 2561-2571, DOI: 10.1007/s00726-015-2047-5

J. Martens-Lobenhoffer*, S-Bode-Böger, B. Clement
First detection and quantification of Nδ-monomethylarginine, a structural isomer of NG-monomethylarginine, in humans using MS3
Analytical biochemistry, 2016, 493, 14-20, DOI: 10.1016/j.ab.2015.10.001

F. Litty, U. Girreser. B. Clement, D. Schade*
An Efficient Synthesis of Optically pure Nδ-Monomethylated L-Arginine and L-Ornithine
Synthesis, 2016, 48 A-G, DOI: 10.1055/s-0035-1561303

T.N. Steinhauer, U. Girreser, C. Meier, M. Cushman, B. Clement*
One-Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold
Chem Eur J. 2016 22(24):8301-8 doi: 10.1002/chem.201600308

B. Plitzko, A. Havemeyer, B. Bork, F. Bittner, R. Mendel, B. Clement*
Defining the Role of the NADH-Cytochrome-b-5 Reductase 3 in the Mitochondrial Amidoxime Reducing Component Enzyme System
Drug Metab Dispos. 2016 44(10):1617-21 doi: 10.1124/dmd.116.071845

B. Clement*, U. Girreser, T.N. Steinhauer, C. Meier, D. Marko, G. Aichinger, I. Kaltefleiter, L. Stenzel, D. Heber, M. Weide, U. Wolschendorf, I. Zebothsen, D. zur Nieden.
11-Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action.
ChemMedChem. 2016 11(19):2155-2170 doi: 10.1002/cmdc.201600199

F.A. Litty, J. Gudd, U. Girreser, B. Clement, D. Schade*
Design, Synthesis, and Bioactivation of O-Glycosylated Prodrugs of the Natural Nitric Oxide Precursor N^ω -Hydroxy-l-arginine
J Med Chem. 2016 59 (17):8030-41 doi: 1021/acs.jmedchem.6b00810

A. Hoffmann, D. Schade, J. Kirchmair, B. Clement, A. Sauerbrei, M. Schmidtke*
Platform for determining the inhibiton profile of neuraminidase inhibitors in an influenza virus N1 background.
J Virol Methods. 2016 237:192-199 doi: 10.1016/j.viromet.2016.09.014

C. Meier, T.N. Steinhauer, F. Koczian, B. Plitzko, K. Jarolim, U. Girreser, S. Braig, D. Marko, A.M. Vollmar, B. Clement*
A Dual Topoisomerase Inhibitor of Intense Pro-Apoptotic and Antileukemic Nature for Cancer Treatment.
ChemMedChem. 2017, 12 (5): 347-352 doi: 10.1002/cmdc.201700026

P. Kalimuthu, A. Havemeyer, B. Clement, C. Kubitza, A. Scheidig, P. V. Bernhardt
Human mitochondrial amidoxime reducing component (mARC): An electrochemical method for identifying new substrates and inhibitors
Electrochemistry Communications, 2017, DOI: 10.1016/j.elecom.2017.10.003
U. Mrowietz, P.J. Morrison, I. Suhrkamp, M. Kumanova, B. Clement
The Pharmacokinetics of Fumaric Acid Esters reveal their in-vivo effects
Trends in Pharmacological Sciences 39, 2018, DOI: 10.1016/j.tips.2017.11.002

J. Schneider, U. Girreser, A. Havemeyer, F. Bittner, B. Clement*
Detoxification of Trimethylamine N-Oxide by the Mitochondrial Amidoxime Reducing Component mARC
Chemical Research in Toxicology, 2017, 31(6), 447-453; DOI: 10.1021.chemrestox.7b00329

C. Ginsel, B. Plitzko, D. Froriep, D. A. Stolfa, M. Jung, C. Kubitza, A. J. Scheidig,, A. Havemeyer and B. Clement*
The Involvement of the Mitochondrial Amidoxime Reducing Component (mARC) in the Reductive Metabolism of Hydroxamic Acids
Drug Metabolism and Disposition, 2018, 46(10), 1396-1402; DOI: 10.1124/dmd.118.082453
*James R. Gilette Award for Drug Metabolism and Disposition Best Paper of 2018 in the Metabolism category

C. Kubitza , C. Ginsel , F. Bittner , A. Havemeyer , B. Clement* , A. J. Scheidig*
T4 lysozyme-facilitated crystallization of the human molybdenum cofactor-dependent enzyme mARC
Acta Crystallographica, 2018, Section F74, 337-344; DOI: 10.1107/S2053230X18006921

C. Kubitza, F. Bittner, C.n Ginsel, A. Havemeyer, B. Clement*, and A. J. Scheidig*
Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes
Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (47) 11958-11963; DOI: 10.1073/pnas.1808576115

Patente (nur solche, die weiterverfolgt wurden)


B. Clement, Methoden zur Behandlung und Prophylaxe der Pneumocystis carinii Pneumonie (PCP) und anderen Erkrankungen sowie Verbindungen und Formulierungen zum Gebrauch bei besagten Methoden, Dt. Patentanmeldung (1993), 4321444.4, PCT/DE 94/00756(1994), weltweite Anmeldung: Europa (0708640; 16.09.1998), USA (5.786.383; 28.06.1998), Japan (38 38 657; 11.08.2006).

B. Clement, Phenanthridinderivate und ihre Herstellung, Dt. Patentanmeldung (1995), 195 38 088.6-44; PCT/DE 96/01958(1996), weltweite Anmeldung: Europa (0873 315 131; 23.04.2003), USA (6.030.981; 29.02.2000).

B. Clement, Phenanthridinderivate und Phenanthridin enthaltende antitumorale Arzneimittel, Dt. Patentanmeldung (2000), 100 54 337.5; PCT/EP01/12665 (2001), weltweite Anmeldung: Europa (1334115;16.05.07), USA (6.747.038132; 08.06.2004).

B. Clement u.a., Hydroxyamidin - und Hydroxyguanidinverbindungen als Urokinase-Hemmstoffe, Dt. Patentanmeldung (2003), 103 23 898.0; PCT/EP2004/005682, weltweite Anmeldung: WO2004103984, Europa (1628965; 01.03.2006), Japan (2007513062; 24.05.2007), USA (erteilt am 27.10.2009, Nr. 7608623) US20060142305.

B. Clement u.a., Substituierte Pyrido[1,2-a]pyrimidin-Verbindungen und ihre Verwendung als NOS-Inhibitoren, Dt. Patentanmeldung (2003), 103 10 106.3; PCT/EP2004/002279, Erteilung: Europa (1603907; 20.04.2004), USA (7,320,980 B2, 22.01.2008).

B. Clement u.a., Verbesserung der Bioverfügbarkeit von Wirkstoffen mit Amidin-funktion in Arzneimitteln, Dt. Patentanmeldung (2006), 10 2006 034 256.9, PCT beendet – nationale Phase, Anmeldung in 38 Ländern, in einigen Ländern erteilt.

B. Clement u.a., Basische Acetophenone als Hemmstoffe von NO-Synthasen, Dt. Patentanmeldung (2006), 10 2006 031 813.7, PCT/DE 2007/001176, Erteilung: Europa (2037904; 25.03.2009), PCT/WO2008003299.

B. Clement u.a., Aminosäurederivate als Arzneistoffe, Dt. Patentanmeldung (2008), 10 2008 007 440.3, PCT beendet – nationale Phase, eingereicht in Europa und 13 weiteren Länder, in einigen Ländern erteilt.

B. Clement u.a., Amidine und Guanidine und deren Derivate zur Behandlung von Krankheiten, Dt. Patentanmeldung (2008) 10 2008 007 381.4, PCT beendet – nationale Phase, Anmeldung in 46 Ländern, in einigen Ländern erteilt.

B. Clement u.a., Inhibitoren der Dimethylarginin Dimethylaminohydrolase zur Behandlung von Krankheiten, Dt. Patentanmeldung (2009) 10 2008 061247, WO2010066239

B. Clement u.a., Verfahren zur verbesserten Bioaktivierung von Arzneistoffen, Dt. Patentanmeldung (2009) 10 2009 004204.0-41, PCT beendet – nationale Phase, eingereicht in Europa und 12 weiteren Ländern.

B. Clement u.a., N-hydroxy-L-arginine derivatives for treatment of diseases related to nitrogen monoxide deficiency (2010), Dt. Patentanmeldung (2009), 10 2009 004 203.2, PCT/WO2010078865

B. Clement u.a., Antibakteriell und antimykotisch wirkende Substanzen (2010), Dt. Patentanmeldung DE 10 2010 055 322, PCT-Anmeldung und Beginn der nationalen Phase.

B. Clement u.a., Hydrazone compositions for treatment of infections with drug resistant mycobacetria (2011), PCT/EP2311457, PCT/WO2011047814

B. Clement u.a., Verbindungen zur Therapie der Influenza / Compounds for the treatment of influenza (2011), Dt. Patentanmeldung DE 10 2011 117 128, PCT-Anmeldung und Beginn der nationalen Phase.

B. Clement u.a., Neue aromatische Heterocyclen, Verfahren zu ihrer Herstellung und Arzneimittel enthaltend neue aromatische Heterocyclen (2012), Dt. Patentanmeldung 10 2012 006 903.0

B. Clement u.a., Oral bioavailable pentamidin prodrugs for the treatment of diseases (2012), PCT/EP2012/064171, PCT beendet – nationale Phase, eingereicht in Europa und 8 weiteren Ländern.

Abgeschlossene Promotionen seit 2002:


BERGER, K., Vergleichende Charakterisierung zweier CYP2D-Enzyme, Kiel 2002.

KARHAN, W., Charakterisierung, Struktur-Aktivitäts-Beziehungen und Mechanismus eines mikrosomalen, N-reduktiven Biotransformationssystems, Kiel 2002.

MAU, S., Studien zur extrahepatischen Reduktion verschiedener N-hydroxylierter Verbindungen, Kiel 2002.

LOPIAN, K., Enzymatische Grundlagen der Aktivierung des Amidoxim- und Ester-Prodrugs Ximelagatran, Kiel 2002.

BRAß, K., Studien zur Charakterisierung der enzymatischen Grundlagen der Biotransformation von Aziden, Kiel 2002.

DETERS, S., Aktivierung von N-hydroxylierten Prodrugs durch mitochondriale Enzyme, Kiel 2002.

NEHLSEN, S., Untersuchungen zum Wirkmechanismus therapeutisch relevanter Hydrazinderivate, Kiel 2002.

KOCK, I., Synthese und Testung von Benzo[c]phenanthridin-Derivaten als potentielle Zytostatika, Kiel 2003.

FRIEDRICH, S., Aktivität und Kinetik eines mikrosomalen CYP2D-Enzyms, Kiel 2004.

BLUHM, U., Entwicklung von Aktivatoren und Inhibitoren der NO-Synthasen, Kiel 2004.

AMSCHLER, J., Reduktiver Arzneistoffmetabolismus von N-Hydroxyamidinen, Hydroxylaminen und Hydroxamsäuren, Kiel 2004.

FRÖHLICH, A.K., Studium neuer Phase-II-Reduktionen von ausgewählten Arzneistoffen mithilfe von Hepatozytenkulturen und UDP-Glucuronyltransferasen, Kiel 2004.

HEBERLING, S., Neue Reduktionen von Oximen und Derivaten durch mirkosomale und mitochondriale Enzyme, Kiel 2004.

MATSCHKE, K., Studien zur Identifizierung eines prodrug-aktivierenden Enzymsystems, Kiel 2004.

ZEBOTHSEN, I., Charakterisierung, Metabolismus und Interaktionspotential zytostatisch wirksamer 6-Aminobenzo[c]phenanthridine, Kiel 2005.

BUß, U.M., Untersuchungen von Pyrido[1,2-a]pyrimidinen und strukturverwandten Verbindungen als Hemmstoffe von NO-Synthasen, Kiel 2006.

HAVEMEYER, A., Mitochondriale Benzamidoximreduktion: Identifizierung des molybdencofaktorabhängigen Enzymsystems, Kiel 2006.

FRIEDRICH, F., Synthese von Stickstoffmonoxid-Synthase-Inhibitoren, Kiel 2007.

BÜHRENHEIDE, A., Pharmakokinetik des Pentoximesters, Kiel 2007.

HOLTKAMP, D., Isolierung eines Prodrug-reduzierenden Enzymsystems aus der Schweineniere, Kiel 2007.

SIEVERS, J., N-Hydroxyguanidinderivate von Neuraminidasehemmstoffen, Kiel 2007.

ZUR NIEDEN, D., Benzo[c]phenanthridine: neue Derivate, zytostatische Wirksamkeit und Verbesserung der Wasserlöslichkeit, Kiel 2007.

REH, R., Untersuchungen zur Beteiligung verschiedener Reduktasen an der Aktivierung von N- und S- oxygenierten Prodrugs, Kiel 2007.

KANZOW, S., Charakterisierung der mikrosomalen Reduktion N-hydroxylierter Verbindungen, Kiel 2008.

KOTTHAUS, Joscha, Metabolismus und Bioverfügbarkeit von Serinprotease Inhibitoren und ihren Amidoxim-Prodrugs, Kiel 2008.

REEH, C., Neue Prodrug-Prinzipien für Amidine, Kiel 2008.

ROSTAMI YAZDI, M., Pharmakokinetik und Pharmakodynamik von Fumarsäureestern, Kiel 2008.

GRÜNEWALD, S., Studien zur Biotransformation N-hydroxylierter Verbindungen durch molybdäncofaktorabhängige Enzymsysteme, Kiel 2008.

KOTTHAUS, Jürke, Substituierte L-Arginin-Derivate als Modulatoren des Stickstoffmonoxid-generierenden Systems, Kiel 2008.

SCHADE, D., Synthese von Stickstoffmonoxid-modulierenden L-Arginin-Derivaten und Prodrugs für Hydroxyguanidine, Kiel 2008.

WUNDT, J., Charakterisierung von NeoHepatozyten als Ersatz für humane Hepatozyten und Induktionsuntersuchungen, Kiel 2008.

HUNGELING, H., Neue Prodrugs von Diamidinen zur Therapie protozoischer Erkrankungen, Kiel 2009.

STENZEL, L., Synthese neuer Benzo[c]phenanthridin-Derivate und deren Stickstoff-Analoga als potentielle Zytostatika, Kiel 2009.

KLEIN, N., Neue Modulatoren des NO-generierenden Systems, Kiel 2010

MOTIKA, M., Structure and function of flavin-containing monooxygenases 3 and 5, Kiel 2010

SCHWERING, U., Transport- und Biotransformationsstudien mit Amidinprodrugs, Kiel 2010.

KEIL, A., Inhibitoren der Dihydropteroinsäuresynthase und der Ribonucleotid Reduktase in Mykobakterium tuberculosis, Kiel 2011.

LUNK, I., Entwicklung neuer Inhibitoren der Enzyme Dimethylarginin, Dimethylaminohydrolase und Arginase, Kiel 2012

KLOSE, S., Untersuchungen zum Wirkmechanismus von 6-Amino-11,12-dihydro-1-(3‘5‘-dimethoxy-4‘ hydroxyphenyl)benzo[c]phenanthridiniumchlorid (BP11) als potentielles Zytostatikum, Kiel 2012

KROMPHOLZ, N., Reduktion von aliphatischen Amidoximen und N-hydroxylierten Basenanaloga durch neue molybdänhaltige Enzymsysteme, Kiel 2013.

FRORIEP, D., Reduktion N-oxygenierter Verbindungen durch die mitochondriale Amidoxim Reduzierende Komponente, Kiel 2013.

COHRS, B., Radiosynthese und Bioverfügbarkeitsstudien mittels in vivo SPECT-Imaging von [123I]-markierten Pentamidin-Prodrugs zur Behandlung der Afrikanischen Schlafkrankheit, Kiel 2013.

OTT, G., Untersuchungen zu genetischen Variationen im mARC-haltigen N-reduktiven Enzymsystemen, Kiel 2013.

ALTMANN, K., Untersuchung der Umsetzung asymmetrisch methylierter Arginine durch rekombinant hergestellte und native Dimethylarginin-Dimethylaminohydrolase-2, Kiel 2014.

JAKOBS, H., Studien zur Verknüpfung der mitochondrialen amidoximreduzierenden Komponente (mARC) mit dem Energiestoffwechsel, Kiel 2014.

MEIER, C., Zur Entwicklung neuer aza-analoger Benzo[c]phenanthridine mit antitumoraler Wirkung, Kiel 2014.

JAKOBS, H., Studien zur Verknüpfung der mitochondrialen amidoximreduzierenden Komponente (mARC) mit dem Energiestoffwechsel, Kiel 2014.

RIEBLING, L., Synthese, in vitro Charakterisierung und in vivo Testung neuer Amidin-Prodrugs, Kiel 2014.

PLITZKO, B., Die Komponenten des mARC-Enzymsystems im N-reduktiven Metabolismus humaner Zellen, Kiel 2014.

KRISCHKOWSKI, C., mARC-Expression und N-reduktive Aktivität in hepatischen und extrahepatischen porcinen und humanen Geweben und Studien zur submitochondrialen Lokalisation von mARC, Kiel 2014.

SCHWARZ, L., Synthese, Charakterisierung und Metabolismus von N,N'-Dihydroxybenzamidinen und N-substituierten Benzamidoximen, Kiel 2015.

BAUCH, E., Untersuchungen zu Struktur-Aktivitäts-Beziehungen am mARC-Enzymsystem, Kiel 2015.

GUDD, J., Evaluierung neuer Prodrugprinzipien für Wirkstoffe mit Amidin- und Guanidinfunktionen, Kiel 2015.

GABEL, S., Untersuchung der Permeabilität und der Biotransformation neuer Amidin-Prodrugs, Kiel 2015.

LITTY, F.A., Synthese und Charakterisierung L-Arginin-abgeleiteter Modulatoren des Stickstoffmonoxid-generierenden Systems, Kiel 2016

STEINHAUER, T.N. Neue isotere stickstoffhaltige Heterozyklen auf Benzo[c]phenanthridin-Basis: Synthetischer Zugang und antitumorale Wirksamkeit, Kiel 2016

GEESE, H., Charakterisierung und Untersuchung neuer JAK-Inhibitoren zur Behandlung chronisch entzündlicher Darmerkrankungen, Kiel 2017