CHEMICAL SYNTHESIS OF ANALOGS OF PLATELET ACTIVATING FACTOR AND ANTIHYPERTENSIVE POLAR RENOMEDULLARY LIPID

Actual and postulated roles of glycerophospholipids in a number of biological systems, processes, and disease states have been increasingly realized. Recently, choline glycerophospholipids, multispecies 1-(fatty)alkyl-2-acetoyl-glycerophosphatidylcholine (AEPC, AEGPC), have been shown to have structures in common with Antihypertensive Polar Renomedullary Lipid (APRL), and also of native Platelet Activating Factor (PAF, 1, representative molecular species). The chemical syntheis of three bioisosteric analogs (2-4) of PAF/APRL (1) was undertaken: 3- 3-(hexadecyloxy)-2-acetoxy)propoxy hydroxyphosphonyl propyl trimethylammonium hydroxide (2); 3- 2-(ethoxy)-3-(hexadecyloxy)-propoxyl hydroxy- phosphonyl propyl trimethylammonium hydroxide (4); and trimethyl (3-phosphonopropyl)ammonium hydroxide, mono-2-acetamido-3-(hexadecyloxy)propyl ester (5). The rationale and design, routes of chemical synthesis, purification, and structure confirmation of these analogs is discussed. The synthesis of a key intermediate, 2-t-butoxy-1-(hexadecyloxy)methyl -ethylamine, has provided a versatile pre- cursor for the preparation of a number of glycerophospholipid-amide analogs, including potential antihypertensive inhibitors of the renin-angiotensin system. Preliminary results indicate that, compared with PAF activity on human platelets in vitro, analog 2 exhibits weak aggregatory and possibly inhibitory activities; the synthetic bioiso- steric lysoglycerophosphatidylcholine analog 3 was inactive in the test system. (UNFORMATTED TABLE FOLLOWS) CH(,2)OCH(,2)(CH(,2))(,14)CH(,3) X-CH O CH(,2)-O-P-Y-CH(,2)CH(,2)N(CH(,3))(,3) OH 1, X = CH(,3)COO, Y = O 2, X = CH(,3)COO, Y = CH(,2) 3, X = HO, Y = CH(,2) 4, X = CH(,3)CH(,2)O, Y = CH(,2) 5, X = CH(,3)CONH, Y = CH(,2) (TABLE ENDS