Studies on bioactive compounds. 13. Synthesis and lack of growth-inhibitory properties of cyclohexane-1,2,4-triol 1,2-diesters, which resemble ring C of the phorbol ester molecule

Abstract

It has been suggested that ring C of biologically active phorbol esters is an essential structural feature of the pharmocophore which confers activity on these compounds. In this study the hypothesis has been tested that compounds which resemble ring C of the phorbol ester molecule mimic the ability of phorbol esters to inhibit cell growth at nontoxic concentrations. All four diastereoisomers of (+/-)-1,2-di-O-octanoylcyclohexane-1,2,4-triol have been prepared from cyclohexen-4-ol and tested for growth-inhibitory and cytotoxic properties. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate inhibited the growth of A549 human lung carcinoma cells by 50% at a concentration of 0.2 nM and exerted cytotoxicity at concentrations of greater than 1 microM. Diacylglycerols are the physiological ligands and activators of protein kinase C, the receptor via which phorbol esters are thought to mediate their effects. The diacylglycerols 1-oleoyl-2-acetylglycerol and 1,2-dioctanoylglycerol and the cyclohexanetriol diesters inhibited the growth of A549 cells only at concentrations of 10(-5) to 10(-4) M, at which they were also cytotoxic. A computer-assisted analysis of the goodness of fit between the cyclohexanetriol diesters and ring C of the phorbol moiety revealed possible energetic grounds for conformational dissimilarities. The results suggest that activation of protein kinase C alone is probably not sufficient to reproduce phorbol ester induced growth arrest in A549 cells and that the cyclohexanetriol diesters may lack pivotal elements of the phorbol ester pharmacophore.