Drug-phospholipid conjugates as potential prodrugs: synthesis, characterization, and degradation by pancreatic phospholipase A(2).
The aim of the present study was the synthesis of phospholipids containing a drug molecule instead of a fatty acid. Valproic acid and ibuprofen served as model compounds. The target molecules were synthesized either starting from sn-glycero-3-phosphocholine (1) or using (S)-2-O-benzyl-1-O-tritylglycerol (11) and (R)-2-O-benzyl-1-O-tert-butyldiphenylsilylglycerol (12), respectively, as key intermediates. With respect to the surface properties and the aggregation behavior, the drug-phospholipid conjugates resembled natural phosopholipids. Upon incubation with porcine pancreatic phospholipase A(2), only compounds with a fatty acid in the sn-2 position of the glycerol backbone were degraded. Derivatives with either ibuprofen in the sn-2 position or displaying the unnatural S-configuration were resistant to enzymatic in vitro hydrolysis.
Kurz
M
M
University of Münster, Department of Pharmaceutical Chemistry, D-48149, Münster, Germany.
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D006868:Hydrolysis; D007052:Ibuprofen / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010179:Pancreas / Q000201:enzymology*; D010741:Phospholipases A / Q000378:metabolism*; D010767:Phosphorylcholine / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014635:Valproic Acid / Q000737:chemistry*
D011355:Prodrugs; D010767:Phosphorylcholine; D014635:Valproic Acid; D010741:Phospholipases A; D007052:Ibuprofen