The group of Prof. Dr. Andreas Kirschning is focused on natural product chemistry employing means and techniques of both chemistry and biology, while another main field of research represents the development of enabling methods in organic synthesis with emphasis on microreactor technology.
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Multiple Organolithium Generation in the Continuous Flow Synthesis of AmitriptylineAdv. Synth. Catal. 2013, 355, 3375-3380.
A continuous flow protocol for the preparation of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chemistry when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous multilithiation combined with carboxylation and the Parham cyclization, a Grignard addition and thermolytic water elimination by inductive heating are key features of the multistep protocol.
[3+2]-Cycloaddiotions of nitrile ylides after photoactivation of vinyl azides under flow conditionsBeilstein. J. Org. Chem. 2013, 9, 1745-1750.
The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal formation of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a [3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles become directly accessible starting from the corresponding vinyl azide.
Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)Angew. Chem. Int. Ed. 2013, 52, 9813-9817.
High-frequency inductive heating and flow chemistry are an ideal match for high-temperature synthesis. This is demonstrated in the multistep flow synthesis of the neurolepticum olanza- pine (Zyprexa) that included three reactions with inductive heating and two purification steps conducted as continuous processes.
Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapyNat. Prod. Rep. 2013, 30, 1299-1323.
In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.
Bioreduction of Aryl Azides during Mutasynthesis of New AnsamitocinsOrg. Lett. 2013, 15, 4442–4445.
Supplementing a culture of a mutant strain of Actinosynnema pretiosum that is unable to biosynthesize aminohydroxy benzoic acid (AHBA), with 3-azido-5-hydroxy-benzoic acid and 3-azido-5-amino-benzoic acid, unexpectedly yielded anilino ansamitocins instead of the expected azido derivatives. This is the first example of the bioreduction of organic azides. The unique nature of these results was demonstrated when 3-azido-5-amino-benzoic acid was fed to the corresponding AHBA blocked mutant of Streptomyces hygroscopicus, the geldanamycin producer. This mutasynthetic experiment yielded the fully processed azido derivative of geldanamycin..
Copper nanoparticles supported on silica coated maghemite as versatile, magnetically recoverable and reusable catalyst for alkyne coupling and cycloaddition reactionsAppl. Catal. A 2013, 455, 39-45.
A versatile and magnetically recoverable catalyst consisting of copper nanoparticles on silica coated maghemite nanoparticles (MagSilica®) is presented. The catalyst has been prepared under mild conditions by fast reduction of anhydrous CuCl2 with lithium sand and a catalytic amount of DTBB (4,4’-di-tert-butylbiphenyl) as electron carrier, in the presence of the magnetic support. The catalyst has been fully characterized and its performance in different coupling and cycloaddition reactions of terminal alkynes has been studied. This new copper-based catalyst has shown to be very efficient and easily reusable in the Glaser alkyne dimerization reaction in THF, the multicomponent Huisgen 1,3-dipolar cycloaddition reaction in water and the three-component synthesis of propargylamines under solvent free conditions.
Two-Step Flow Synthesis of Biarylmethanes by Reductive Arylation of TosylhydrazonesJ. Flow Chem. 2013, 3, 11-16.
The coupling of tosylhydrazones derived from aldehydes or ketones with aryl boronic acids to yield the corresponding arylation products that was first developed in the group of Barluenga was achieved in a two-step flow protocol. Starting from the respective carbonyl compounds, tosylhydrazones were formed in the first flow step. These were directly transferred into the second reactor to be coupled with boronic acids. Remarkably, carbenes are postulated to be the highly reactive intermediates of this reaction. Both steps required heating which was managed by electromagnetic induction of a fixed bed material based on steel beads. A continuously conducted two-step flow processes over a period of almost 2 days gave the arylation product in 84% yield.
Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptideBeilstein J. Org. Chem. 2013,9, 270–277.
Covalent multistep coating of poly(methylpentene), the membrane material in lung ventilators, by using a copper-free “click” approach with a modified cyclic RGD peptide, leads to a highly biocompatible poly- (methylpentene) surface. The resulting modified membrane preserves the required excellent gas-flow properties while being densely seeded with lung endothelial cells.
Fully defined in situ cross-linkable alginate and hyaluronic acid hydrogels for myocardial tissue engineeringBiomaterials 2013, 34, 940–951.
Despite recent major advances including reprogramming and directed cardiac differentiation of human cells, therapeutic application of in vitro engineered myocardial tissue is still not feasible due to the inability to construct functional large vascularized contractile tissue patches based on clinically applicable and fully defined matrix components. Typical matrices with preformed porous 3D structure cannot be applied due to the obvious lack of migratory capacity of cardiomyocytes (CM). We have therefore developed a fully defined in situ hydrogelation system based on alginate (Alg) and hyaluronic acid (HyA), in which their aldehyde and hydrazide-derivatives enable covalent hydrazone cross-linking of polysaccharides in the presence of viable myocytes. By varying degrees of derivatization, concentrations and composition of blends in a modular system, mechanophysical properties of the resulting hydrogels are easily adjustable. The hydrogel allowed for the generation of contractile bioartificial cardiac tissue from CM-enriched neonatal rat heart cells, which resembles native myocardium. A combination of HyA and highly purified human collagen I led to significantly increased active contraction force compared to collagen, only. Therefore, our in situ cross-linking hydrogels represent a valuable toolbox for the fine-tuning of engineered cardiac tissue's mechanical properties and improved functionality, facilitating clinical translation toward therapeutic heart muscle reconstruction.
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Ph.D. studentships available
There are currently Ph.D. studentships available in the area of microbiological chemistry in the research group of Professor Russell Cox.