René Frank

University of Leipzig, Leipzig, Saxony, Germany

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Publications (19)61.61 Total impact

  • Pure and Applied Chemistry 01/2015; 87(2). DOI:10.1515/pac-2014-1006 · 3.11 Impact Factor
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    ABSTRACT: Peptidic ligands selectively targeting distinct G protein-coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor-preferring analogues of neuropeptide Y (NPY) bind and activate the human Y1 receptor subtype (hY1 receptor), which is found in 90 % of breast cancer tissue and in all breast-cancer-derived metastases. Herein, novel highly boron-loaded Y1-receptor-preferring peptide analogues are described as smart shuttle systems for carbaboranes as 10B-containing moieties. Various positions in the peptide were screened for their susceptibility to carbaborane modification, and the most promising positions were chosen to create a multi-carbaborane peptide containing 30 boron atoms per peptide with excellent activation and internalization patterns at the hY1 receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi-carbaborane peptide into hY1-receptor-expressing cells, exceeding the required amount of 109 boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron-containing moieties.
    ChemMedChem 01/2015; 10(1). DOI:10.1002/cmdc.201402368 · 3.05 Impact Factor
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    ABSTRACT: Carbaboranes are increasingly used as pharmacophores to replace phenyl substituents in established drug molecules. In contrast to traditional organic chemistry, elaborated procedures to introduce functionality frequently fail in the case of carbaboranes and their chemistry is often hampered by degradation of the cluster. Herein, the development of a one-pot synthesis of a water-soluble N-nido-dicarbaborato indole is presented, including a proposed mechanism for the reaction sequence. These studies provide useful synthetic tools for the conjugation of two important pharmacophores, indoles and carbaboranes.
    Dalton Transactions 11/2014; 44(4). DOI:10.1039/C4DT03218G · 4.10 Impact Factor
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    ABSTRACT: Substitution of the dicarbaundecaborate anion nido-7,8-C2 B9 H12 (-) (1) by precise hydride abstraction followed by nucleophilic attack usually leads to symmetric products 10-R-nido-7,8-C2 B9 H11 . However, thioacetamide (MeC(S)NH2 ) as nucleophile and acetone/AlCl3 as hydride abstractor gave asymmetric 9-[MeC(NHiPr)S]-nido-7,8-C2 B9 H11 (2), whereas N,N-dimethylthioacetamide (MeC(S)NMe2 ) gave the expected symmetric 10-[MeC(NMe2 )S]-nido-7,8-C2 B9 H11 (4). For the formation of 2, acetone and thioacetamide are assumed to give the intermediate MeC(S)N(CMe2 ) (3), which then attacks 1 with formation of 2. Similarly, reaction of acetyliminium chloride [MeC(O)NH(CPh2 )]Cl (5) with 1 in THF gave a mixture of 9- and 10-substituted [MeC(NHCHPh2 )O]-nido-7,8-C2 B9 H11 (6 and 7, respectively). These reactions are the first examples in which compounds (here heterodienes) that unite the functionalities of both hydride acceptor and nucleophilic site react with 1 in a bimolecular fashion. Furthermore, the analogous reaction of 1 and 5 (in an equilibrium mixture with acetyl chloride and benzophenone imine) in MeCN afforded 10-[MeC(NCPh2 )NH]-nido-7,8-C2 B9 H11 (8) and MeC(O)NHCHPh2 (9).
    Chemistry - A European Journal 01/2014; 20(5):1440-6. DOI:10.1002/chem.201303762 · 5.70 Impact Factor
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    ABSTRACT: New phosphorus-containing, five-membered P,P,P and P,N,P heterocycles were synthesized and fully characterized. The P,P,P heterocycles, 1,2,3-triphospholanes, can be synthesized by two different facile pathways, whereas the P,N,P compound, a 1-aza-2,5-diphospholane, can only be obtained with silylamine.
    Chemistry - A European Journal 12/2013; 20(5). DOI:10.1002/chem.201302878 · 5.70 Impact Factor
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    ABSTRACT: Substitution at the dicarbaborate anion nido-7,8-C2B9H12− (1) with precise hydride abstraction leads to symmetric products 10-R-nido-7,8-C2B9H11, e.g., 10-[cyclo-(CH2)4O]-nido-7,8-C2B9H11 (2) and 10-[cyclo-(CH2)4S]-nido-7,8-C2B9H11 (3). However, this approach has been limited to acetaldehyde as hydride acceptor in an acidified, aqueous two-phase system. In expanding the concept of hydride abstraction, we have found that acetone, activated by AlCl3, is capable of accepting hydride with substitution of the symmetric B10 position in the presence of suitable donor molecules (Lewis bases). Thus, by employing a one-phase water-free system, 2 and 3 as well as moisture-sensitive 10-CH3CN-nido-7,8-C2B9H11 (4) were obtained in good to high yield. Reactions with 1 in neat acetone gave 10-HO-nido-7,8-C2B9H11− (7). An alternative reagent for hydride abstraction in 1 is tritylium tetrafluoroborate (Ph3CBF4), which gave 10-Ph2S-nido-7,8-C2B9H11 (11) in the presence of Ph2S. The Ph2S moiety in 11 could easily be replaced by pyridine and triethylamine, giving 10-C5H5N-nido-7,8-C2B9H11 (12) and 10-Et3N-nido-7,8-C2B9H11 (13). Additionally, reactions of 1 with CF3SO3H in the presence of CH3CN or CH3SCN gave 9-CH3C(NH2)-nido-7,8-C2B9H11 (5) and 9-CH3SC(NH2)-nido-7,8-C2B9H11 (6) by electrophilic substitution.
    Journal of Organometallic Chemistry 12/2013; 747. DOI:10.1016/j.jorganchem.2013.04.031 · 2.30 Impact Factor
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    ABSTRACT: The first terminal organometallic alkylphosphanylidenetantalum(V) complexes [Cp*Ta{1,2-(NSiMe3)2C6H4}(PR)] were obtained with cyclohexyl (2) and isopropyl groups (3) at phosphorus, whereas adamantyl and tert-butyl substituents resulted in the formation of the paramagnetic tantalum(IV) complex [Cp*Ta{1,2-(NSiMe3)2C6H4}Cl] (4). DFT studies showed that the terminal cyclohexyl and isopropyl phosphanylidene complexes are stable towards dimerization and dissociation.
    Berichte der deutschen chemischen Gesellschaft 06/2013; 2013(18). DOI:10.1002/ejic.201300500
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    ABSTRACT: Short selective neuropeptide Y (NPY) analogs are highly attractive because of their facile synthesis. Based on the reduced-size NPY analog [Pro(30), Nle(31), Bpa(32), Leu(34)]NPY 28-36 position 32 was identified as a key position to alter the preferential activation pattern of the human neuropeptide Y receptors (hYRs). By replacing benzoylphenylalanine (Bpa) by a biphenylalanine (Bip) the photostability was first improved while the biological activity was maintained. SAR-studies showed that both aromatic rings have a high influence on the preferential hYR subtype activation. Interestingly, replacement of Bpa(32) by a strongly hydrophobic moiety changed the hYR subtype preference of the analog. Whereas the parent compound is able to activate the human neuropeptide Y(1) receptor (hY(1)R) subtype, the introduction of an N(ε)-ortho-carbaboranyl propionic acid modified lysine resulted in a loss of activity at the hY(1)R but in an increased activity at both the hY(2)R and the hY(4)R. However, subsequent receptor internalization studies with this novel analog revealed that receptor internalization can neither be triggered at the hY(2)R nor at the hY(4)R suggesting a biased ligand. Surprisingly, investigations by (1)H NMR spectroscopy revealed structural changes in the side chains of residues Pro(30) and Leu(34) which nicely correlates with the shift from hY(1)R/hY(4)R to hY(2)R/hY(4)R activation preference. Thus, position 32 has been identified to switch the bioactive conformation and subsequently influences receptor subtype activation behavior.
    Neuropeptides 01/2013; DOI:10.1016/j.npep.2012.12.001 · 2.55 Impact Factor
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    ABSTRACT: In medicinal chemistry, carbaboranes can be employed either as boron carriers for boron neutron capture therapy (BNCT) or as scaffolds for radiodiagnostic or therapeutic agents. We have developed a suitable synthesis employing the phosphoramidite method to connect meta-carbaboranyl bis-phosphonites with the 6'-OH group of isopropylidene-protected galactose, followed by oxidation or sulfurization to give the corresponding bis-phosphonates. Deprotection yielded water-soluble compounds. The corresponding disodium salts exhibit especially low cytotoxicity. Preliminary results on the in vivo toxicity and biodistribution of two compounds in mice indicated a lack of selectivity for the cotton rat lung (CRL) tumor chosen for the experiment. For the incorporation of carbaboranes into breast tumor-selective modified neuropeptide Y, [F-7, P-34]-NPY, a synthesis of a carbaborane-modified lysine derivative was developed. Linkage of the lysine to the boron cluster was achieved by using a propionic acid spacer. Incorporation of the amino acid derivatives into NPY and [F-7, P-34]-NPY by solid-phase peptide synthesis was successful. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained. Asborin, the carbaborane analogue of aspirin, is a rather weak inhibitor of cyclooxygenase-1 (COX-1) and COX-2, but a highly potent aldo/keto reductase 1A1 (AKR1A1) inhibitor. Modification either at the carboxyl group or at the chlorophenyl ring in indomethacin with ortho- and meta-carbaboranyl derivatives gave active derivatives only for the ortho-carbaborane directly attached to the carboxyl group, while the corresponding adamantyl and meta-carbaboranyl derivatives were inactive.
    Pure and Applied Chemistry 05/2012; 84(11):2289-2298. DOI:10.1351/PAC-CON-11-11-02 · 3.11 Impact Factor
  • ChemPlusChem 05/2012; 77(5). DOI:10.1002/cplu.201200013 · 3.24 Impact Factor
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    ABSTRACT: The potential of 1,2-dicarba-closo-dodecaborane(12)-9-thiol, 9-HS-1,2-closo-C2B10H11, for the design of novel building blocks is highlighted by two examples envisioned for incorporation into tumor-selective peptides for boron neutron capture therapy (BNCT). By employing a t-Bu protection strategy the synthesis of a bis-galactosyl-substituted ortho-carbaborane carboxylic acid was elaborated, and the procedure is suggested as a general approach towards carbaboranes with three substituents. Furthermore, a simple route to a tris(ortho-carbaborane) building block starting from pentaerythritol is illustrated. All compounds were synthesized in moderate to high yields and identified by 1H, 11B, and 13C NMR spectroscopy, IR spectroscopy, mass spectrometry, and in one case by X-ray crystallography.
    Polyhedron 05/2012; 39(1):9-13. DOI:10.1016/j.poly.2012.03.003 · 2.05 Impact Factor
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    ABSTRACT: Sulfenyl chlorides RSCl (R = p-C(6)H(4)OMe, Ph, p-C(6)H(4)NO(2), CN or 2-C(5)H(4)N) react with 7,8-nido-C(2)B(9)H(12)(-) with asymmetric substitution on the pentagonal C(2)B(3) face to give 9-RS-7,8-nido-C(2)B(9)H(11)(-) (R = p-C(6)H(4)OMe (3), Ph (4), p-C(6)H(4)NO(2) (5), CN (6)) and the zwitterion 9-(S-2-C(5)H(4)NH)-7,8-nido-C(2)B(9)H(11) (7), respectively, in high yield, while tBuSCl did not react and S(2)Cl(2) led to decomposition. Further reaction of 5-7 with iodine gave the corresponding iodo derivatives NMe(4) [9-I-11-RS-7,8-nido-C(2)B(9)H(10)] (R = p-C(6)H(4)NO(2) (8), CN (9)) and the zwitterion 9-I-11-(S-2-C(5)H(4)NH)-7,8-nido-C(2)B(9)H(11) (10), respectively. Compounds 3-10 were fully characterised by (1)H, (11)B, (11)B{(1)H}, (13)C{(1)H} spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis, 3-7 also by (11)B-(11)B{(1)H} COSY NMR spectroscopy and 8-10 by X-ray structure determination.
    Dalton Transactions 04/2012; 41(20):6155-61. DOI:10.1039/c2dt12501c · 4.10 Impact Factor
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    Chemistry - A European Journal 05/2011; 17(22):6034-8. DOI:10.1002/chem.201002146 · 5.70 Impact Factor
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    ABSTRACT: Nontoxic ortho-carbaborane is one of the most promising structure for boron neutron capture therapy (BNCT). For directed uptake of ortho-carbaborane by tumor cells, receptor-subtype selective neuropeptide Y (NPY) and its derivatives were modified with ortho-carbaborane. The derivative [F(7), P(34)]-NPY has been shown to be a breast cancer selective ligand that binds to the Y(1)-receptor subtype, whereas [Ahx(5-24)]-NPY selectively addresses Y(2)-receptor subtypes that are found in neuroblastoma cells. ortho-Carbaboranyl propionic acid was synthesized and linked to the ε-amino group of N(α)-Fmoc protected L-lysine. The characterization of the compounds was performed by NMR, IR, and MS studies. The carbaborane-modified amino acid was incorporated into NPY, [F(7), P(34)]-NPY, and [Ahx(5-24)]-NPY by an optimized solid phase peptide synthesis using Fmoc protection. Binding studies and IP accumulation assays confirmed nanomolar affinity and activity of the modified analogues despite of the large carbaborane cluster. Internalization studies revealed excellent and receptor subtype specific uptake of the conjugates into respective cells.
    Journal of Medicinal Chemistry 03/2011; 54(7):2368-77. DOI:10.1021/jm101514m · 5.48 Impact Factor
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    ABSTRACT: The 1:1 or 1:2 stoichiometric reaction of [Na2(thf)4(P4Mes4)] (1; Mes = 2,4,6-Me3C6H2) with [{RhCl(cod)}2] (cod = 1,5-cyclooctadiene) gave a mixture of compounds of which [Na(thf)3][Rh(P3Mes3)(cod)] (2) with a trimesityltriphosphane-1,3-diide ligand was structurally characterized. Density functional calculations on 2 confirmed the structural parameters obtained by X-ray diffraction studies. Shared electron number and natural bond orbital analyses indicated only weak interactions between Na and P, which were found to be even weaker than the Na–Rh interactions with covalent contribution. When an excess of 1 was used (3:1 or 4:1), 2 was also obtained as the major product together with small amounts of the side-products cyclo-P6Mes6 (3) and [Na3(Et2O)(P4Mes4)(PHMes)]∞ (4). Compounds 3 and 4 were only characterized by single-crystal X-ray diffraction studies. Their formation indicates that the reaction includes the breaking and making of P–P bonds to give (P3Mes3)2–, PHMes–, and cyclo-P6Mes6, although the mechanism is unclear. Furthermore, the reaction of 1 with 2 equiv. of [AgCl(PPh3)2] gave the tetranuclear compound [Ag4(P6Mes6)2] (5) in which the novel (P6Mes6)2– ion also indicates degradation of the P4 chain followed by P–P bond formation.
    European Journal of Inorganic Chemistry 02/2011; 2011(5):739--747. DOI:10.1002/ejic.201001137 · 2.97 Impact Factor
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    ABSTRACT: The synthesis of chiral ortho-carbaboranyl bis(aminohalophosphines) is presented, and spectroscopic and crystallographic data of these compounds are discussed. Furthermore, their reactivity toward alcoholysis was investigated. Quantum chemical calculations showed that the inhibition of methanolysis is of kinetic and not of thermodynamic origin. The disubstitution of the carbaboranes leads to P...P interactions as strong as a hydrogen bond that extremely lower the rate of the methanolysis.
    Inorganic Chemistry 07/2009; 48(13):6072-82. DOI:10.1021/ic900443c · 4.79 Impact Factor
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    ABSTRACT: Enantiomerically pure (RP,RP)- and (RP,SP)-1,2-bis[1-adamantyloxy-(–)-menthyloxyphosphanyl]-closo-dicarbaborane(12), 1,2-bis[bis(–)-menthyloxyphosphanyl]-closo-dicarbaborane(12)and 1,2-bis[bis(4-tert-butylphenyloxy)phosphanyl]-closo-dicarbaborane(12) were synthesised by the reaction of dilithiated 1,2-dicarba-closo-dodecaborane(12) with two equivalents of the corresponding chlorophosphite. The phosphonites are stable towards epimerisation, oxygen and water. P···P through-space coupling was observed, and the 3JPP coupling constants were determined by spectral simulation and DFT calculations. Late transition-metal complexes with molybdenum and rhodium were prepared to study the coordination properties of the bis(phosphanyl)carbaborane(12) compounds. Catalytic properties of various rhodium complexes were investigated in homogeneous catalytic hydroformylation reactions with various olefins. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
    Berichte der deutschen chemischen Gesellschaft 07/2009; 2009(19):2776 - 2788. DOI:10.1002/ejic.200900304
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    ABSTRACT: Mn(III) and Mo(IV)-Salen complexes homogeneous and immobilized on a silica surface have been tested in the catalytic epoxidation of cyclooctene and cyclohexene with tert-butylhydroperoxide (TBHP) and hydrogen peroxide (HP) as an oxidant. The effects of reaction conditions on the epoxide yield as well as the epoxidation rate with different catalysts have been established. The catalytic decomposition of TBHP by manganese and molybdenum-Salen complexes has been studied. The peptide immobilized Salen complexes were compared in catalytic activity with ester bound ones. The immobilized catalysts show stable catalytic activity in manifold reuses. The Mo-Salen complexes homogeneous as well as immobilized exhibited high catalytic activity for the epoxidation of cyclooctene, whereas Mn-Salen complex systems cause additionally non-productive decomposition of hydroperoxide.
    Journal of Molecular Catalysis A Chemical 08/2007; 273(1-2):250-258. DOI:10.1016/j.molcata.2007.04.010 · 3.68 Impact Factor