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.
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 diterpene 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.
Adolf
W
W
German Cancer Research Center, Institute of Biochemistry, Heidelberg.
Seip
E H
EH
Hecker
E
E
Dossaji
S F
SF
D000818:Animals; D002273:Carcinogens / Q000302:isolation & purification*; D055598:Chemical Phenomena; D002621:Chemistry; D004224:Diterpenes; D007509:Irritants / Q000302:isolation & purification*; D007928:Lethal Dose 50; D051379:Mice; D010947:Plants, Toxic / Q000032:analysis*; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000302:isolation & purification*
D002273:Carcinogens; D004224:Diterpenes; D007509:Irritants; D013729:Terpenes; C011309:mezerein