Publications
2021
Stereocontrolled synthesis of pseurotin A2. Jachak, G.; Tharra, P. R.; Sevelda, P.; Švenda, J.*
J. Org. Chem. 2021, 86, 11845−11861.
We report synthesis of two diastereomeric structures previously proposed for the complex secondary metabolite pseurotin A2. Both structures were accessed from the same building blocks taking advantage of a stereodivergent nickel(II)–diamine-catalyzed 1,4-addition of a chiral 2-alkoxycarbonyl-3(2H)-furanone. Late-stage Csp–Csp3 cross-coupling of a highly functionalized bromoalkyne featured in the pseurotin A2 side-chain assembly. The work supports the 2016 stereochemical revision of pseurotin A2 and represents the first chemical synthesis of this natural product.
Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core. Němec, V.; Maier, L.; Berger, B.-T.; Chaikuad, A.; Drápela, S.; Souček, K.; Knapp, S.; Paruch, K.*
Eur. J. Med. Chem. 2021, 215, 113299.
The furo[3,2-b]pyridine motif represents a relatively underexplored central pharmacophore in the area of kinase inhibitors. Herein, we report flexible synthesis of 3,5-disubstituted furo[3,2-b]pyridines that relies on chemoselective couplings of newly prepared 5-chloro-3-iodofuro[3,2-b]pyridine. This methodology allowed efficient second-generation synthesis of the state-of-the-art chemical biology probe for CLK1/2/4 MU1210, and identification of the highly selective inhibitors of HIPKs MU135 and MU1787 which are presented and characterized in this study, including the X-ray crystal structure of MU135 in HIPK2.
Cytoprotective activities of kinetin purine isosteres. Maková, B.; Mik, V.; Lišková, B.; González, G.; Vítek, D.; Medvedíková, M.; Monfort, B.; Ručilová, V.; Kadlecová, A.; Khirsariya, P.; Gándara Barreiro, Z.; Havlíček, L.; Zatloukal, M.; Soural, M.; Paruch, K.; D'Autréaux, B.; Hajdúch, M.; Strnad, M.; Voller, J.*
Bioorg. Med. Chem. 2021, 33, 115993.
Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.
Paruch, K.; Carbain, B.; Havel, S.; Damborský, J.; Brezovský , J.; Daniel, L.; Sisáková, A.; Nikulenkov, F.; Krejčí, L. Substituted aminothiazoles as inhibitors of nucleases. EP 3556755
The present invention relates to substituted aminothiazoles as inhibitors of nucleases, especially nuclease MRE11 and MRE11-containing complexes, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as cancer and other genome instability associated diseases.