René Frank

University of Leipzig, Leipzig, Saxony, Germany

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Publications (19)68.63 Total impact

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    ABSTRACT: The cobalt bis(dicarbollide) complex, [commo-3,3´-Co(1,2-C2B9H11)2]-, has captured much attention for biochemical and medical purposes, in particular for the treatment of tumors by boron neutron capture therapy (BNCT). Derivatives of cobalt bis(dicarbollide) are commonly prepared by ring-opening reactions of cyclic oxonium ions, and thus the respective products are usually charged. Furthermore, attempts to incorporate cobalt bis(dicarbollide) into peptides are rare despite obvious advantages. Herein, the synthesis of an imidazolium-based charge-compensated cobalt bis(dicarbollide) building block, which allows additional modifications with moieties of biochemical relevance, such as monosaccharides, is reported. Furthermore, conjugates of these building blocks with the Y1 receptor-selective derivative of neuropeptide Y ([F7,P34]-NPY) retained excellent response to hY1 receptors found to be over-expressed in breast tumors and metastases.
    No preview · Article · Dec 2015 · ChemBioChem
  • René Frank · Evamarie Hey-Hawkins
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    ABSTRACT: In the treatment of cancer, boron neutron capture therapy (BNCT) is a mild and promising alternative to established harsh therapeutic methods such as chemo- and radiation therapy. However, successful BNCT procedures strongly depend on efficient, tumour-selective boron-delivery systems, and recently we have demonstrated that the breast tumour-selective peptide [F7,P34]-NPY is a promising boron-shuttle system after conjugation with three ortho-carbaborane clusters (1,2-closo-C2B10H10). The extreme hydrophobicity of the latter, however, causes problems in medicinal applications invivo. Therefore, we have elaborated a synthetic protocol towards a deoxygalactosyl-modified (and thus more hydrophilic) building block that can readily be conjugated with the shuttle peptide. A key intermediate, i.e., ortho-carbaborane functionalised with a bis-isopropylidene-protected deoxygalactosyl moiety, was synthesised by both a silyl protection strategy (which is generally recommended for monosubstitution) and direct reaction of metallated ortho-carbaborane in acceptable yield.
    No preview · Article · Aug 2015 · Journal of Organometallic Chemistry
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    ABSTRACT: Dicarba-closo-dodecaboranes(12) (C2B10H12, carbaboranes) are highly hydrophobic and stable icosahedral carbon-containing boron clusters. The cage framework of these clusters can be modified with a variety of substituents, both at the carbon and at the boron atoms. Substituted carbaboranes are of interest in medicine as boron neutron capture therapy (BNCT) agents or as pharmacophores. High and selective accumulation in tumour cells is an important requirement for a BNCT agent and is achieved by incorporating boron-rich, water-soluble carbaborane derivatives into breast tumour-selective modified neuropeptide Y, [F7, P34]-NPY. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained. Use of carbaboranes as pharmacophores was shown by replacement of Bpa32 (Bpa = benzoylphenylalanine) in the reduced-size NPY analogue [Pro30, Nle31, Bpa32, Leu34]-NPY 28-36 by ortho-carbaboranyl propanoic acid. The inclusion of the carbaborane derivative resulted in a short NPY agonist with an interesting hY2R/hY4R preference. This might be a promising approach in the field of anti-obesity drug development.
    No preview · Article · Feb 2015 · Pure and Applied Chemistry
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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.
    Preview · Article · Jan 2015 · ChemMedChem
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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.
    Preview · Article · Nov 2014 · Dalton Transactions
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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).
    No preview · Article · Jan 2014 · Chemistry - A European Journal
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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.
    No preview · Article · Dec 2013 · Chemistry - A European Journal
  • René Frank · Henry Auer · Evamarie Hey-Hawkins
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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.
    No preview · Article · Dec 2013 · Journal of Organometallic Chemistry
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    ABSTRACT: The first terminal organometallic alkylphosphanylidenetantalum(V) complexes [Cp*Ta{1,2-(NSiMe3)2C6H 4}(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-(NSiMe 3)2C6H4}Cl] (4). DFT studies showed that the terminal cyclohexyl and isopropyl phosphanylidene complexes are stable towards dimerization and dissociation. The first terminal organometallic alkylphosphanylidenetantalum(V) complexes are obtained with cyclohexyl and isopropyl groups at phosphorus, whereas adamantyl and tert-butyl substituents result in the formation of a paramagnetic tantalum(IV) complex. DFT studies show that the terminal cyclohexyl and isopropyl phosphanylidene complexes are stable towards dimerization and dissociation.
    No preview · Article · Jun 2013 · Berichte der deutschen chemischen Gesellschaft
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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.
    Full-text · Article · May 2012 · Pure and Applied Chemistry
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    ABSTRACT: A complex matter: Na[cyclo-(P 5tBu 4)] reacts with two equivalents of [MnBr(CO) 5] to give the phosphorus-rich manganese(I) complex [Mn 2(μ-Br)-{cyclo-(P 4tBu 3)PtBu}(CO) 6] (see structure) containing a [{cyclo-(P 4tBu 3)}PtBu]-ligand. The rearrangement of [cyclo-(P 5tBu 4)]- to [cyclo-(P 4tBu 3)PtBu]- was rationalized by theoretical studies. Thermolysis of up to 1000°C gives Mn 2P.
    No preview · Article · May 2012 · ChemPlusChem
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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.
    No preview · Article · May 2012 · Polyhedron
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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.
    No preview · Article · Apr 2012 · Dalton Transactions
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    ABSTRACT: In the past decades a lot of progress has been achieved in the design of miniaturized systems. For instance, the manufacture of computer chips employing optical technologies, for example, phototemplating, is well established. However, optical procedures are limited to approximately 50 nm. Alternatively, nanostructures may be formed by means of self assembly systems. Besides the arrangement of the molecular building blocks by hydrogen bonds or inorganic metal-ligand bonds, unexpected strong chalcogen-chalcogen interactions or halogen bonds have captured interest as connectors. A large number of selective locks and keys increase the variety of possible complex structures. However, the utility of strong nonbonding interactions is not solely limited to the nanoscale. A targeted arrangement of these linkers even allows the design of self-healing rubberlike materials. These selected examples illustrate the importance to gain knowledge of directional molecular interactions
    Full-text · Article · May 2011 · Chemistry - A European Journal
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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.
    Full-text · Article · Mar 2011 · Journal of Medicinal Chemistry
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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.
    Full-text · Article · Feb 2011 · European Journal of Inorganic Chemistry
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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.
    Full-text · Article · Jul 2009 · Inorganic Chemistry
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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)
    No preview · Article · Jul 2009 · Berichte der deutschen chemischen Gesellschaft
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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.
    No preview · Article · Aug 2007 · Journal of Molecular Catalysis A Chemical