Irritant Principles of the Mezereon Family (Thymelaeaceae), V. New Skin Irritants and Tumor Promoters of the Daphnane and 1α-Alkyldaphnane Type from Synaptolepis kirkii and Synaptolepis retusa

Abstract

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.

Traditional preparation of Phaleria nisidai, a Palauan tea, reduces exposure to toxic daphnane-type diterpene esters while maintaining immunomodulatory activity

“…Similarly, acetoxyhuratoxin and huratoxin have anticancer activity (Abe et al, 1998;Weijan, 1992) contrasted with irritant and tumor-promoting activity Hecker, 1984, 1975;Adolf et al, 1988). Simplexin, acetoxyhuratoxin and huratoxin are known to be acutely toxic, and sometimes deadly, to livestock by damaging the gastrointestinal tract and causing heart failure (Fletcher et al, 2009;Roberts et al, 1975;Wilson et al, 2007).…”

Daphnane-Type Diterpene Orthoesters and their Biological Activities

“…Mellerin (35) was isolated from the leaves of Neoboutonia melleri (Euphorbiaceae) [28], and synaptolepis factor K8 (25) was found in the roots of Synaptolepis spp. (Thymelaeaceae) as a weak irritant to the mouse ear [26]. From Baliospermum montanum [34] as well as from Cunuria spruceana [35], Gnidia kraussiana [36] and Diarthron vericulosum [29], montanin (38) revealed to have antileukaemia, anticancer and piscicidal activities.…”

“…Further daphnetoxin-analogues were isolated from various plants belonging to the Excoecaria, Wikstroemia and Synaptolepsis species [22][23][24]26,29,[38][39][40][41][42][43]80]. The strong irritant and tumor promoting activity of synaptolepsis factor K7 (23) is worth mention [26].…”

“…The strong irritant and tumor promoting activity of synaptolepsis factor K7 (23) is worth mention [26]. This compound is also a very potent neurotrophic agent [44], and show nM-level anticancer activity in human leukaemia cells [45].…”

Medicinal plants of euphorbiaceae occurring and utilized in thailand. V. Skin irritants of the daphnane and tigliane type in latex of Excoecaria bicolor and the uterotonic activity of the leaves of the tree

“…Free Excoecaria factors of the 5P-hydroxyresiniferono1-6a,7a-epoxide-9,13,14-orthoester type (If) may exhibit tumour promoting activity, depending on the orthoester moiety: the decanoate Ig (simplexin, SIM) and the (2E)-hexadecenoate Ih were strongly active (Adolf et al, 1988), whereas the 2,4,6-decatrienoate [Excoecaria factor B4 (lc)], was inactive . Also Excoecaria factors of the 12-deoxyphorbol (3)-and the 4,12-dideoxyphorbol(5)-13-ester type [e.g.…”