Conformationally constrained analogues 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

Abstract

In the present investigation, the last two possible modes of generating conformationally semirigid diacylglycerol (DAG) analogues embedded into five- membered ring lactones as templates III and IV are investigated. The first two templates studied in previous investigations corresponded to 2- deoxyribonolactone (template I) and 4,4-disubstituted γ-butyrolactone (template II), with the latter producing potent protein kinase C (PK-C) ligands with low nanomolar binding affinities. The templates reported in this work correspond to 2,3-dideoxy-L-erythro- or -threo-hexono-1,4-lactone (template III) and 2-deoxyapiolactone (template IV). Compounds constructed with the dideoxy-L-erythro- or -threo-hexono-1,4-lactone template were synthesized stereospecifically from tri-O-acetyl-L-glucal and L-galactono- 1,4-lactone, respectively. Compounds constructed with the 2-deoxyapiolactene template were synthesized stereoselectively from di-O-isopropylidene-α-D- apiose. Inhibition of the binding of [3H]phorbol-12,13-dibutyrate to PK-Cα showed that only the threo-isomer, 5-O-tetradecanoyl-2,3-dideoxy-L-threo- hexono-1,4-lactone(2)was a good PK-Cligand (K(i) = 1 μM). The rest of the ligands had poorer affinities with K(i) values between 10 and 28 μM. With these results, the order of importance of five-membered ring lactones as competent templates for the construction of semirigid DAG surrogates with effective PK-C binding affinity can be established as II >> I ~ IIl> IV.