Synthesis of a novel modular scaffold for cysteine-derived lipid analogues as tissue targeting ligands

This thesis describes the design and preparation of a modular scaffold for the facile synthesis of diverse lipopeptides with specific receptor-targeting sequences. The prepared lipopeptides will be incorporated in liposomal formulations in hopes to improve drug delivery via binding affinity to αvβ3 integrin receptors that are over-expressed on human breast cancer cells. A novel class of lipid analogues were developed from L-cysteine via cyclocondensation with m-nitrobenzaldehyde and acryloylation with acryloyl chloride yielding a trifunctionalized thiazolidine core with carboxylic acid, aryl nitro, and acryloyl substituents. The core was used to generate an array of compounds in a highly modular process with hydrophobic units for binding to nanoparticles, ligand units with linkers for binding to target tissues, and fluorophores for localization studies. The fatty component was appended via conjugate addition of thiol analogues to the acrylamide functionality of the core and the aryl nitro group was reduced to the corresponding amine followed by conjugation to a fluorophore or Fmoc protection, which yields a novel cysteine lipid analogue (CLA). We demonstrate the application of the CLA construct for the synthesis of lipopeptides via solid-phase peptide synthesis (SPPS). With this synthetic technology the CLA construct can be readily utilized in the preparation of an array of custom lipopeptides bearing targeting sequences for drug delivery systems. Future work consists of utilizing the novel targeting CLA liposomal formulations for in vitro and in vivo studies to verify the improvement of drug delivery and binding affinity for αvβ3 integrin receptors in cancer cells.