Irritant principles of the mezereon family (Thymelaeaceae) , V. New skin irritants and tumor promoters of the daphnane and 1 alpha-alkyldaphnane type from Synaptolepis kirkii and Synaptolepis retusa
Adolf, W.; Seip, E.H.; Hecker, E.; Dossaji, S.F.
Journal of Natural Products 51(4): 662-674
1988
ISSN/ISBN: 0163-3864 PMID: 3210015 Document Number: 313178
Seventeen mostly new, skin irritant diterpene esters (DTE) of the daphnane and 1.alpha.-alkyldaphnane types were isolated from roots of Synaptolepis kirkii and Synaptolepis retusa. The parent alcohols of the daphnane types are shown to be 5.beta.-hydroxyresiniferonol-6.alpha.,7.alpha.-oxide [1] and 5.beta., 12.beta.-dihydroxyresiniferonol-6.alpha., 7.alpha.-oxide [2]. Ten of the daphnane types are 9,13-14-orthoesters and three are conventional esters involving tertiary or secondary hydroxyl groups at C-13 or C-14, respectively. The latter may be considered immediate precursors of corresponding orthoesters. The four 1.alpha.-alkyldaphnane types are intramolecular 9,13,14-ortho-(2-hexadecenoic acid)-esters in which, formally, the second to last C atom of the orthoester moiety is linked covalently to C-1.alpha. of the diterpene parent alcohols 1 or 2. Thus, in the new structure, a macrocyclic ring bridges the .alpha. side of the diterpine moiety in an "ansa" type manner. The irritancies on the mouse ear of the DTE obtained cover a wide range (I24 = 0.05-670 nmole-1). Some of them are considerably more irritant than the daphnane type standard simplexin. Structure/activity investigations reveal that an ester group instead of a free hydroxyl group at C-20 ("cryptic types"), or presence of a hydroxy or an acetoxy group in position 12 diminishes the irritancies of the daphnane types isolated, similar to what is known in corresponding tigliane types. In the standardized initiation/promotion protocol on the back skin of mice, some of the irritant DTE exhibit tumor-promoting activities higher than that of simplexin.