Synthesis of acid-labile diplasmenyl lipids for drug and gene delivery applications.
The low pH environments characteristic of endosomal compartments and ischemic tissues provide an intrinsic pathway for triggering site-specific contents release from appropriately designed delivery vehicles. Accordingly, research in this group has focused on the design, synthesis and application of novel acid-sensitive lipids that will undergo facile lamellar (L alpha) to hexagonal (HII) phase transitions within these acidic sites. Previously, it has been demonstrated that plasmenylcholine-type lipids have excellent acid hydrolysis and contents release kinetics (Gerasimov et al., Biochim. Biophys. Acta. 1324 (1997) 200-214; Rui et al., J. Am. Chem. Soc. 120 (1998) 11213-11218). This paper describes the synthesis of three new acid sensitive lipids, based on a chiral 1,2-di-O-(1Z',9Z'-octadecadienyl)-sn-glycerol (6) platform, displaying phosphocholine (7), poly(ethyleneoxide) (8), and O-carbamoyl-N-diethylen-etriamine (10) headgroups. Intermediate 6 was obtained in 28% overall yield via a six step synthesis from (S)-(+)-2,2-dimethyl-1,2-dioxolane-4-methanol. Subsequent conversion to the final products was acheived in moderate (7 and 10) to excellent yields (8).
Boomer
J A
JA
Department of Chemistry, Purdue University, West Lafayette, IN 47907-1393, USA.
Thompson
D H
DH
D000143:Acids / Q000737:chemistry; D002855:Chromatography, Thin Layer; D016503:Drug Delivery Systems; D008055:Lipids / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D014162:Transfection / Q000379:methods*
D000143:Acids; D008055:Lipids