Ondřej Baszczyňski Research Group

Department of Organic Chemistry, Charles University, Prague

Research

Phosphate based drug delivery vehicles: prodrugs & self immolative chemistry

We work on a phosphate based prodrugs to improve undesired properties of common drugs such as absorption, distribution, off-target effects and toxicity. The prodrug-concept is based on chemical modification of original drug molecule in a way of attaching a promoiety (chemical group) to mask the active drug, which helps original drugs to overcome pharmacological barriers. Our phosphate-based promoieties are designed to be activated enzymatically or chemically in the target cells after administration into the body. Self-immolative (SI) linkers has a special place in drug delivery and construction of smart materials and polymers with application towards diagnostics and cell imaging. Basic idea behind this approach is using cascade disassembling linker to connect two or more different moieties with different function. SI constructs consist of a cleavable group connected to a core (linker) which binds a leaving moiety. The cleavable group prevents the core from spontaneous disassembling, and, depending on the chemical nature of the cleavable group, it can be triggered via enzymatic, redox, chemical or photochemical activation. After activation, the leaving moiety is released as a consequence of SI core fragmentation.

Our approach to study self-immolation among P-based linkers

We focuse on a several series of P-based linkers to study their self-immolation for the purpose of finding the best candidates for both rapid (on-sight action) and slow (e.g. retarded tablets) drug release: Initially, we screen various linkers and their effect on cyclization rate. We are using a light-triggered photocaging group as a good starting point to study the self-immolation process, which we monitor in situ by 31P NMR. We also want to develop a universal set of linkers, designed for a specific cargo (drug) type that would release different cargos at optimal rates.

Targeted antifungal compounds, prodrugs, and fungal probes

Treatment of systemic fungal mycoses is complex, and a limited number of antifungal drugs represents a challenge in treating invasive fungal infections. Moreover, currently used antifungal drugs have many limitations, including serious adverse effects (off-target toxicity), undesired and hardly predictable drug-drug interactions, and poor pharmacological properties. To decrease the toxicity of current antifungals, we aim for targeted antifungal-drug delivery based on modified azoles or amphotericin B (currently used ”old” antifungals). We are working on several series of conjugable antifungals, prodrugs, and solvatochromic probes to study their influence on fungal susceptibility and integrity of fungal cell walls. We also plan to evaluate the potential of these drugs to serve as targeting moieties in the construction of targeted drug delivery vehicles.

Proposed conjugable antifungals, prodrugs, and solvatochromic probes to study & fight pathogenic fungi.

 

Phosphorus chemistry

Phosphorus is a unique element utterly crucial in nature, especially biology. Our passion (and addiction:) is to study various organic reactions incorporating phosphorus. Apart from our linker projects, we are interested in developing new approaches to integrate phosphorus into organic molecules using transition metal catalysis to form C−P bonds. We also aim for P-derived sugars as potential inhibitors of various enzymes.

Phosphorus chemistry in our lab

Recent publications

Cover page and cover profile in Chemistry A European Journal https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202102216

06/ Phosphate-based Self-Immolative Linkers for delivery of Amine-Containing Drugs. Dud, M.; Tichotová, M.; Procházková, E.; Baszczyňski, O. Molecules 2021, 26(17), 5160. https://www.mdpi.com/1420-3049/26/17/5160

05/ Phosphate-based Self-Immolative Linkers for Tuneable Double Cargo Release. Šimon, P.; Tichotová, M.; Gallardo, M. G.; Procházková, E.; Baszczyňski, O. Chem. Eur. J. 2021, 27(50), 12763–12775. https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.202101805

04/ NMR Structure Elucidation of Naphthoquinones from Quambalaria cyanescens. Procházková, E.; Kucherak, O.; Stodůlková, E.; Tošner, Z.; Císařová, I.; Flieger, M.; Kolařík, M.; Baszczyňski, O. J. Nat. Prod. 2021, 84(1), 46–55. https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.0c00930

03/ Phosphate linkers with traceable cyclic intermediates for self-immolation and detection and monitoring
Procházková, E.; Šimon, P.; Straka, M.; Filo, J.; Májek, M.; Cigáň, M.; Baszczyňski, O. Chem. Commun. 2021, 57, 211-214. https://pubs.rsc.org/en/content/articlelanding/2021/cc/d0cc06928k

02/ Sterically-Controled Self Immolation in Phosphoramidate Linkers Triggered by Light. Procházková, E.; Jašík, J.; Cigáň, M.; Baszczyňski, O. Eur. J. Org. Chem. 2020, 7, 897-906. https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201901882

01/ Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane. Procházková, E.; Navrátil, R.; Janeba, Z.; Roithová, J.; Baszczyňski, O. Org. Biomol. Chem. 2019, 17(2), 315-320. https://pubs.rsc.org/en/content/articlelanding/2019/ob/c8ob02870b

Current members

Head: Dr. Ondřej Baszczyňski
Scientists/PostDocs: Dr. Rafael Navrátil, Dr. Aneta Ešnerová

Ph.D. students: MSc. Vahid Barati

Current members

Mgr. Students: Bc. Tereza Kárníková, Bc. Lukáš Taraj

Bc. Students: Lucie Černá, Kateřina Faldíková

Former members

Scientists/Postdocs: Dr. Ondřej Štepánek, Dr. Mateja Dud, Dr. Oleksandr Kucherak

Students: Jordan Francoise (Erasmus, France), María García Gallardo (Erasmus, Spain)

Funding / Collaboration

Fun
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