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KIRSCHNING GROUP

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Latest publications

L. L. Wang,  A. Kirschning:

Total synthesis of elansolids B1 and B2

Beilstein J. Org. Chem. 2017, 13, 1280-1287

graphabstr.jpgThe elansolids A1-A3, B1, and B2 are secondary metabolites formed by the gliding bacterium Chitinophaga sancti. They show antibacterial activity against Gram-positive bacteria. A second generationtotal synthesis of the antibiotic elansolid B1 (2) and the
first synthesis of elansolid B2 (3) are reported. In contrast to previous work, the (Z,E,Z)-triene at C10-C15 was assembled by using an optimized C-C cross-coupling sequence with a Suzuki cross-coupling reaction as key step.

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L. L. Wang, D. Candito,  G. Dräger, J. Herrmann, R. Müller, A. Kirschning:

Harnessing a p-Quinone Methide Intermediate in the Biomimetic Total Synthesis of the Highly Active Antibiotic 20-Deoxy-Elansolid B1

Chem. Eur. J. 2017, 23, 5291-5298.

350-graphabstr.jpgThe polyketide, 20-deoxy elansolid B1, was prepared by a convergent strategy that relied on a putative biomimetic intramolecular Diels–Alder cycloaddition (IMDA) via a vinylic p-quinone methide intermediate to furnish the key tetrahydroindane unit. The (Z,E,Z)-configured triene unit was constructed by Pd-catalyzed Suzuki–Miyaura and Stille crosscoupling reactions without isomerization of any of the olefinic double bonds. Formation of a p-methide quinone intermediate under basic conditions and subsequent Michael addition by water to this intermediate proceeded with high facial selectivity which terminated this total synthesis. Remarkably, the new elansolid derivative 2c shows very good inhibitory effect against Bacillus subtilis and Staphylococcus aureus (including MRSA) similarly to the best elansolid derivatives reported so far. Consequently, the hydroxyl group at C20 is not essential for antibacterial activity.

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L.-L. Wang, A. Balakrishnan, N.-C. Bigall, D. Candito, J.F. Miethe, Y. Xie, K. Seidel, M. Ott, A. Kirschning:

A bio-chemosynthetic approach to superparamagnetic iron oxide - ansamitocin conjugates for use in magnetic drug targeting (MDT)

Chem. Eur. J. 2017, 23, 2265–2270.

350-2.jpgHot and toxic! The combination of muta- and semisynthesis yields a modified toxic ansamitocin, which was loaded to functionalized super-paramagnetic, nanostructured particles. The toxin (IC50 in the lower nanomolar range) was released in an external electromagnetic field through inductive heating. The conjugate concept allows the combination of hyperthermia with chemotherapy in anticancer research.

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S. Ceylan, H. C.-H. Law, A. Kirschning, P. H. Toy:

Organocatalytic Alkyne Isomerizations under Flow Conditions Using Heterogeneous Bifunctional Polystyrene Bearing Phosphine and Phenol Groups

Synthesis 2017, 49, 145-150.

flow350.jpgA heterogeneous bifunctional polymer bearing phosphine and phenol groups was developed to catalyze the isomerization of electronically activated alkynes. This organocatalytic process provided the corresponding (E,E)-dienes and was shown to work under both batch and flow conditions. 

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R. Sharma, S. Mohammadi-Ostad-Kalayeh, F. Stahl, C. Zeilinger, G. Dräger, A. Kirschning, P.C. Ravikumar:

Two new labdane diterpenoids and one new β-lactam from the aerial parts of Roylea cinerea

Phytochem. Lett. 2017, 19, 101-107.

roylea200.jpgTwo new labdane diterpenoids cinereanoid C (1), cinereanoid D (2), a new β-lactam, cinerealactam E (3) as well as six known flavonoid glycosides (4–9) were isolated from the aerial parts of Roylea cinerea (Lamiaceae). The structures of (1–9) were all determined by MS, IR and NMR spectroscopy. The structure of cinereanoid D (2) was further proven by single crystal X-ray diffraction. Six known flavonoid glycosides (4–9) were also isolated for the first time from this plant. 2, 5, 6 and 7 were found to significantly inhibit the ATP binding of a tumour growth-promoting heat shock protein, Hsp90. 

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N. Dibbert, A. Krause, J.-C. Rios-Camacho, I. Gruh, A. Kirschning, G. Dräger:

A Synthetic Toolbox for the In Situ Formation of Functionalized Homo- and Heteropolysaccharide- Based Hydrogel Libraries

Chem. Eur. J. 2016, 52, 18777-18786.

toolbox350.jpgA synthetic toolbox for the introduction of aldehydo and hydrazido groups into the polysaccharides hyaluronic acid, alginate, dextran, pullulan, glycogen, and carboxymethyl cellulose and their use for hydrogel formation is reported. Upon mixing differently functionalized polysaccharides derived from the same natural precursor, hydrazone cross-linking takes place, which results in formation of a hydrogel composed of one type of polysaccharide backbone. Likewise, hydrogels based on two different polysaccharide strands can be formed after mixing the corresponding aldehydo- and hydrazido-modified polysaccharides. A second line of these studies paves the way to introduce a biomedically relevant ligand, namely, the adhesion factor cyclic RGD pentapeptide, by using an orthogonal click reaction. This set of modified polysaccharides served to create a library of hydrogels that differ in the combination of polysaccharide strands and the degree of cross-linking. The different hydrogels were evaluated with respect to their rheological properties, their ability to absorb water, and their cytotoxicity towards human fibroblast cell cultures. None of the hydrogels studied were cytotoxic, and, hence, they are in principal biocompatible for applications in tissue engineering. 

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T. Pfeffer, F. Sasse, C. F. Schmidt, S. Lakämpfer, A. Kirschning, T. Scholz:

The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function

Eur. J. Med. Chem. 2016, 112, 164-170.

tonantzitolone-pfeffer350.jpgTonantzitlolone A, a diterpene isolated from the Mexican plant Stillingia sanguinolenta, shows cytostatic activity. Both the natural product tonantzitlolone A and its synthetic enantiomer induce monoastral spindle formation in cell experiments which indicates inhibitory activity on kinesin-5 mitotic motor molecules. These inhibitory effects on kinesin-5 could be verified in in vitro single-molecule motility assays, where both tonantzitlolones interfered with kinesin-5 binding to its cellular interaction partner microtubules in a concentration-dependent manner, yet with a larger effect of the synthetic enantiomer. In contrast to kinesin-5 inhibition, both tonantzitlolone A enantiomers did not affect conventional kinesin-1 function; hence tonantzitlolones are not unspecific kinesin inhibitors. The observed stronger inhibitory effect of the synthetic enantiomer demonstrates the possibility to enhance the overall moderate anti-proliferative effect of the lead compound tonantzitlolon A by chemical modification.

 

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