Publications
2018
Preparation of 3,4-substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles. Havel, Š.; Khirsariya, P.; Akavaram, N.; Paruch, K.; Carbain, B.*
J. Org. Chem. 2018, 83, 15380.
3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared, properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.
Enantioselective conjugate additions of 2-alkoxycarbonyl-3(2H)-furanones. Vojáčková, P.; Chalupa, D.; Prieboj, J.; Nečas, M.; Švenda, J.*
Org. Lett. 2018, 20, 7085−7089.
Enantioselective conjugate additions of in situ generated 2-alkoxycarbonyl-3(2H)-furanones to three distinct types of π -electrophiles (terminal alkynones, α -bromo enones, and α -benzyl nitroalkenes) are reported. Catalysis by a nickel(II) − diamine complex provided alkynone-derived adducts with high enantioselectivity, preferentially as the Z-isomers, and completely suppressed the undesired O-alkylation pathway. A cupreidine-based catalyst enabled extension of the enantioselective conjugate additions to α -bromo enones and α -benzyl nitroalkenes. The densely functionalized adducts that result are useful precursors to synthetic analogs of spirocyclic natural products pseurotins.
Impact of access tunnel engineering on catalysis is strictly ligand-specific: Mutations show inverse effects on branched and linear haloalkanes. Kaushik, S.; Marques, S.; Khirsariya, P.; Paruch, K.; Libichová, L.; Brezovský, J.; Prokop, Z.; Chaloupková, R.*; Damborský, J.*
FEBS Journal 2018, 285, 1456.
The traditional way of rationally engineering enzymes to change their biocatalytic properties utilizes the modifications of their active sites. Another emerging approach is the engineering of structural features involved in the exchange of ligands between buried active sites and the surrounding solvent. However, surprisingly little is known about the effects of mutations that alter the access tunnels on the enzymes’ catalytic properties, and how these tunnels should be redesigned to allow fast passage of cognate substrates and products. Thus, we have systematically studied the effects of single-point mutations in a tunnel-lining residue of a haloalkane dehalogenase on the binding kinetics and catalytic conversion of both linear and branched haloalkanes. The hotspot residue Y176 was identified using computer simulations and randomized through saturation mutagenesis, and the resulting variants were screened for shifts in binding rates. Strikingly, opposite effects of the substituted residues on the catalytic efficiency toward linear and branched substrates were observed, which was found to be due to substrate-specific requirements in the critical steps of the respective catalytic cycles. We conclude that not only the catalytic sites, but also the access pathways must be tailored specifically for each individual ligand, which is a new paradigm in protein engineering and de novo protein design. A rational approach is proposed here to address more effectively the task of designing ligand-specific tunnels using computational tools.
Paruch, K.; Petrůjová, M.; Němec, V. Furopyridines as inhibitors of protein kinases. US 9902733 B2
(also JP 6386585 and EP 2940022 B1)
The invention relates to furo[3,2-b]pyridines substituted at least in position 5 as inhibitors of protein kinases, regulators or modulators, methods of preparation thereof, pharmaceutical compositions containing the compounds, and pharmaceutical use of the compounds and compositions in the treatment of the diseases such as, for example, cancer or neurodegenerative diseases.
Damborsky, J.; Nikulenkov, F.; Sisáková, A.; Havel, Š.; Krejčí, L.; Carbain, B.; Brezovsky, J.; Daniel, L.; Paruch, K. Pyrazolotriazines as inhibitors of nucleases. US 9969741 B2
(also EP 2957562 B1 and JP 6313906)
The invention relates to furo[3,2-b]pyridines substituted at least in position 5 as inhibitors of protein kinases, regulators or modulators, methods of preparation thereof, pharmaceutical compositions containing the compounds, and pharmaceutical use of the compounds and compositions in the treatment of the diseases such as, for example, cancer or neurodegenerative diseases.