CONFORMATIONALLY CONSTRAINED ANALOGS OF DIACYLGLYCEROL .13. PROTEIN-KINASE-C LIGANDS BASED ON TEMPLATES DERIVED FROM 2,3-DIDEOXY-L-ERYTHRO(THREO)-HEXONO-1,4-LACTONE AND 2-DEOXYAPIOLACTONE

In the present investigation, the last two possible modes of generatin g conformationally semirigid diacylglycerol (DAG) analogues embedded i nto five-membered ring lactones as templates III and IV are investigat ed. The first two templates studied in previous investigations corresp onded to 2-deoxyribonolactone (template I) and 4,4-disubstituted gamma -butyrolactone (template II), with the latter producing potent protein kinase C (PK-C) ligands with low nanomolar binding affinities. The te mplates reported in this work correspond to 2,3-dideoxy-L-erythro- or -threo-hexono-1,4-lactone (template III) and 2-deoxyapiolactone (templ ate IV). Compounds constructed with the dideoxy-L-erythro- or -threo-h exono-1,4-lactone template were synthesized stereospecifically from tr i-O-acetyl-L-glucal and L-galactono-1,4-lactone, respectively. Compoun ds constructed with the 2-deoxyapiolactone template were synthesized s tereoselectively from di-O-isopropylidene-alpha-D-apiose. Inhibition o f the binding of [H-3]phorbol-12,13-dibutyrate to PK-C alpha showed th at only the threo-isomer, tradecanoyl-2,3-dideoxy-L-threo-hexono-1,4-l actone (2) was a good PK-C ligand (K-i = 1 mu M). The rest of the liga nds had poorer affinities with K-i values between 10 and 28 mu M. With these results, the order of importance of five-membered ring lactones as competent templates for the construction of semirigid DAG surrogat es with effective PK-C binding affinity can be established as II much greater than I similar to III > IV.