New Phorbol and Deoxyphorbol Esters: Isolation and Relative Potencies in Inducing Platelet Aggregation and Erythema of Skin

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Abstract
Diester diterpenes based upon phorbol, 4-deoxyphorbol, 4.alpha.-deoxyphorbol, 4-deoxy-5-hydroxyphorbol and 4,20-dideoxy-5-hydroxyphorbol were isolated from the fruit oil of Sapium indicum. Corresponding tri- and tetra-esters were produced by acetylation and mono-estera by selective hydrolyisis. Compounds (26) were tested for production of erythema in vivo and induction of human and rabbit platelet aggregation in vitro. The flatter shape of the AB-ring trans compounds is necessary for interaction of phorbol-esters at their receptor in that the cis analogs were inactive. The tertiary C-4 hydroxy group of phorbol was not necessary for activity although the 4-deoxy derivatives were less potent than the 4-hydroxy diterpenes. A primary hydroxy group at C-20 was essential for biological activity because the methyl and aldehyde derivatives of this position were inactive. The C-20 acetates were also inactive on platelets, but they did produce erythema, possibly because of the removal of the ester due to lipase activity in the skin. 5-Hydroxy-analogs which undergo intramoleuclar hydrogen bonding had greatly reduced activities in both systems. Membrane stabilizers, phospholipase A2 and calmodulin inhibitors were antagonists for phorbol esters in platelet aggregation tests, while cyclo-oxygenase inhibitors and free radical scavengers had no inhibitory effects. Consequently, one electron withdrawal and free radical formation plays no part in the biological activity of these compounds.