1 Department of Chemistry, Technical University of Denmark
Synthesis, Biophysical Characterization and Biological Studies of Enzyme Sensitive Phospholipid Prodrugs
In the first part of the thesis the work towards a new generation of liposomal drug delivery systems for anticancer agents is described. The drug delivery system takes advantage of the elevated level of secretory phospholipase A2 (sPLA2) IIA in many tumors and the enhanced permeability and retention (EPR) effect. The liposomes consists of sPLA2 IIA sensitive phospholipids having anticancer drugs covalently attached to the sn-2 position of the glycerol backbone in the phospholipids, hence drug leakage is avoided from the carrier system. Various known anticancer agents, like chlorambucil, all-trans retinoic acid, α-tocopheryl succinate and calcitriol were examined for their ability to be incorporated into the investigated drug delivery system and syntheses of the phospholipid prodrugs are described. The majority of the phospholipid prodrugs were able to form particles with diameters close to 100 nm upon extrusion at 20 °C indicating that unilamellar vesicles are formed. When subjected to sPLA2 the phospholipid prodrugs were converted into cytotoxic lysolipids and along with the released anticancer drug a chemotherapeutic cocktail is formed. Cytotoxicity studies in several cancer lines revealed that upon sPLA2 triggering the formulated phospholipid prodrugs displayed IC50 values in range from 3–36 μM and complete cell death was observed when higher drug concentrations were applied. Promising for the drug delivery system the majority of the phospholipid prodrugs remain non-toxic in the absence of the enzyme meaning the prodrugs will not damage healthy tissue during the transport in the body. In the second part of the thesis the synthetic studies towards a library of small naturalproduct- like molecules are described. The collection of molecules was synthesized via a diversity oriented synthesis (DOS) based strategy using a limited number of reaction types. Upon coupling of unsaturated building blocks ring closing metathesis cascades were used to “reprogram” the molecular scaffold and highly diverse structures were obtained. In total 20 novel compounds with a broad structural diversity were prepared in 5 or 6 synthetic steps.