On the active principles of the spurge family, X. Skin irritants, cocarcinogens, and cryptic cocarcinogens from the latex of the manchineel tree

Abstract

From the hydrophobic fraction of the latex of Hippomane mancinella, weak or nonirritant mixtures of esters of polyfunctional diterpene parent alcohols of the tigliane and daphnane types were isolated belonging to the structural type of "cryptic" irritants. The cryptic factor group M'z (tigliane type) represents 12-deoxyphorbol-13,20-diesters, and the cryptic factor groups M'y and M'x (daphnane type) represent mixtures of 9,13,14-orthoesters-20-esters of resiniferonol and 5 beta-hydroxyresiniferonol-6 alpha,7 alpha-oxide, respectively. All of them carry in the 20-position homologous long-chain fatty acids, ranging from C15 to C26. They may be "activated" by mild transesterification reactions yielding corresponding irritant factor groups with free hydroxyl functions at C-20. From the hydrophilic fraction of the latex, the irritant factor M3 (tigliane type) and the factor group Mx (daphnane type) were isolated. According to spectral data, factor M3 represents the 13-(hexadeca-2,4,6-trienoic acid) ester of the parent 12-deoxy-5 beta-hydroxyphorbol-6 alpha,7 alpha-oxide. Factor group Mx consists of two esters inseparable by tlc (silica gel). One is identical with huratoxin; the other represents a hexadeca-2,4,6-trienoic acid orthoester. Mx is also obtained by transesterification of M'x and exhibits irritant and tumor-promoting activity comparable to that of TPA. Some aspects on structure activity relations are deduced from selected chemical-reaction products of factor group Mx.