We work with drug delivery systems (prodrugs). Our passion is design and synthesis of novel drug delivery vehicles (DDV) aimed for targeted drug delivery. Core of our work consist of phosphate based DDVs and their synthesis, self-cleavage/drug release monitoring and optimization. Optimized prodrugs will be used for targeted delivery of therapeutics to the desired site of action (tissue, cell, organ). We are also interested in biologically active compounds, phosphorus chemistry and fluoroprobes.
PhD, MSc and Bc positions available!!! (deadline for PhD applications, March 2019)
WE WANT YOU! Our newly set up (young-and-progressive groupJ) is constantly searching for new colleagues to broaden our community. Our research is aimed towards bioorganic and medicinal chemistry of biologically active compounds and their delivery. Contact us via email: baszczyonatur.cuni.cz or visit us directly in the lab 140.
Optimization of phosphate-based spacers for drug delivery of biologically active compounds
Our phosphate-based spacers (inspired by ProTide prodrug technology, tenofovir (HIV), sofosbuvir (HCV)) consist of phosphate core equipped with: Arm A protected with capping unit – responsible for cyclization reaction; Arm B – responsible for changing the electrophilicity on phosphorus; and the leaving group – represented by drug/cargo (Scheme 1). Capping unit - recognition part - should carry a chemical group/unique ligand, which is recognized by specific binding site or alternatively a photoremovable group.
Scheme 1: phosphate-based spacers construct
Mode of action of phosphate-based spacers is based on activation of a specific capping unit, followed by a self-cleavage (SC) core fragmentation (spontaneous cyclization) and cargo release (Scheme 2). During our studies the capping unit is activated either by light, chemically or enzymatically.
Scheme 2. Mode of action of phosphate-based spacers
The ultimate goal of our spacer approach is to deliver compound of interest to specific sites (organ, tissue) in the patient, in certain time, to provide a quick and effective on-site release of the drug, which is important for direct action. Model spacers are studied by NMR spectroscopy and, alternatively, by the enzyme-based assays. The spacer quality can be evaluated according to the characteristics of its SC process. A good spacer has to fulfil several important criteria: a) spacer must be stable under physiological conditions; b) spacer self-cleavage process must be effective in releasing the cargo load quantitatively; c) After triggering, the SC process must be quick for biological applications in order to release the cargo at the particular site of action.