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)^
NANCY CARMEN MOTOLA,
"CHEMICAL SYNTHESIS OF ANALOGS OF PLATELET ACTIVATING FACTOR AND ANTIHYPERTENSIVE POLAR RENOMEDULLARY LIPID"
Dissertations and Master's Theses (Campus Access).