MEDICINAL CHEMISTRY

doc. Mgr. Kamil Paruch, Ph.D.

E-mail: kamil.paruch@fnusa.cz

Key words

Organic Synthesis, Medicinal Chemistry, Chemical Biology, Kinases, Nucleoside Analogs, Nucleases.

Research focus

The research in our laboratory focuses on development of synthetic methods and strategies for preparation of structurally non-trivial small molecules for applications in biomedical research. Specifically, our project includes:
Development of potent inhibitors of certain „non-routine“ kinases (CLK, HIPK).
Synthesis of new forskolin-based modulators of adenylyl cyclases
Identification inhibitors of selected DNA repair pathways (nucleases Mre11 and Mus81).
Preparation of new small-molecules probes of cell differentiation, and fluorescent probes for biological systems.
Organic synthesis of small-molecule organic compounds of medium complexity.
Medicinal chemistry – optimization of early leads.

Main goals

Total synthesis of new analogs of forskolin and testing their activity against human adenylyl cyclases.
dentification of new inhibitors targeting underexplored protein kinases.
SAR development around the existing proprietary inhibitors of nucleases MRE11 and Mus81; identification of sub-micromolar inhibitors.
Synthesis and biological profiling of new carbocyclic C-nucleosides.

Technological equipment

HPLC with UV, MS and CAD detection
NMR spectrometer
microwave reactor
high pressure reactor
automatic purification systems

Assistant

Mgr. Gabriela Pavlíková
E-mail: gabriela.pavlikova@fnusa.cz

Team members

doc. Mgr. Kamil Paruch, Ph.D.
Mgr. Gabriela Pavlíková
Bc. Klára Kejdová
Mgr. Lukáš Maier, Ph.D.
Mgr. Jakub Švenda, Ph.D.
Pawel Szczepanik, MSc

Selected results

Khirsariya, P.; Pospíšil, P.; Maier, L.; Boudný, M.; Babáš, M.; Kroutil, O.; Mráz, M.; Vácha, R.; Paruch, K. Synthesis and profiling of highly selective inhibitors of methyltransferase DOT1L based on carbocyclic C-nucleosides. J. Med. Chem. 2022, 65, 5701.

Tharra, P. R.; Mikhaylov, A.; Švejkar, J.; Gysin, M.; Hobbie, S. N.; Švenda, J. Short synthesis of (+)-actinobolin: Simple entry to complex small-molecule inhibitors of protein synthesis. Angew. Chem. Int. Ed. 2022, 61, e202116520.

Němec, V.; Maier, L.; Berger, B.-T.; Chaikuad, A.; Drápela, S.; Souček, K.; Knapp, S.; Paruch, K. Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core. Eur. J. Med. Chem. 2021, 215, 113299.

Vojáčková, P.; Michalska, L.; Nečas, M.; Shcherbakov, D.; Bottger, E. C.; Šponer, J.; Šponer, J.; Švenda, J. Stereocontrolled Synthesis of (−)-Bactobolin A. J. Am. Chem. Soc. 2020, 142, 7306.

Boudný, M.; Zemanová, J.; Khirsariya, P.; Borský, M.; Verner, J.; Černá, J.; Oltová, A.; Šeda, V.; Mráz, M.; Jaroš, J.; Kašparková, M.; Jašková, Z.; Spunarová, M.; Brychtová, Y.; Souček, K.; Drápela, S.; Mayer, J.; Paruch, K.; Trbušek, M. Novel Chk1 inhibitor MU380 exhibits significant single-agent activity in TP53-mutated chronic lymphocytic leukemia cells. Haematologica 2019, 104, 2443.

Němec, V.; Hylsová, M.; Maier, L.; Flegel, J.; Sievers, S.; Ziegler, S.; Schröder, M. Berger, B.-T.; Chaikuad, A.; Valčíková, B.; Uldrijan, S.; Drápela, S.; Souček, K.; Waldmann, H.; Knapp, S.; Paruch, K. Furo[3,2-b]pyridine: A novel privileged scaffold for highly selective kinase inhibitors and effective modulators of the Hedgehog pathway. Angew. Chem. Int. Ed. 2019, 58, 1062.