Stereospecific synthesis of antitumor active thioether PAF analogs.
A novel stereospecific synthesis of antitumor active thioether analogs of platelet-activating factor (PAF) is reported. The synthesis is based upon: i) the use of D-serine to provide the chiral center for the construction of the optically active phospholipid molecule; ii) development of the sn-1-thioalkyl function via thioacetate displacement of methanesulfonate-activated primary hydroxyl group followed by alkylation of the sn-1-thiolate function; and iii) introduction of the phosphocholine moiety through the 2-chloro-2-oxo-1,3,2-dioxaphospholane/trimethylamine sequence. The entire scheme relies on the use of a single protecting group. The synthetic thioether phospholipid 1-S-hexadecyl-2-N-acetamidodeoxy-sn-glycero-3-phosphocholine has been shown to be a potent antitumor active phospholipid, exhibiting tumor cytotoxicity against a lymphoblastoid lymphoma (Li-A) cell line and a malignant histiocytic (DHL-4) cell line of human origin at the same level of potency as ET-18-OMe and 1-O-octadecyl-2-N-acetamidodeoxy-sn-glycero-3-phosphocholine. The synthetic method described has a great deal of flexibility, providing a convenient general route to a wide range of thioether PAF analogs.
Bhatia
S K
SK
Department of Chemistry, California State University, Northridge 91330.
Hajdu
J
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D015195:Drug Design; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009904:Optical Rotation; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000737:chemistry; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor