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

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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-deoxyapiolactone 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-C ligand (Ki = 1 μM). The rest of the ligands had poorer affinities with Ki 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 ∼ III > IV.