Antileukaemic properties of 12-hydroxydaphnetoxin derivatives

Plant Orthoesters

“…Contrary to the inactivity of 12-hydroxydaphnetoxin, three 12-acyloxydaphnetoxins, gnidicin ( 50 ), gnididin ( 58 ), and gniditrin ( 60 ) showed potent in vivo antileukemic activities against P388 leukemia in mice at the level of 0.02−0.1 mg/kg . Extensive SAR studies against P388 leukemia showed that the presence of a 12-acyloxy group was a prerequisite for in vivo antileukemic activity, and the activity would normally be enhanced if this group possessed unsaturated double bonds . The fact that 30 and 32 with a 12-benzoyloxy were more potent as topo I inhibitors than those DDOs with an aliphatic 12-acyloxy group was also consistent with this observation.…”

Daphnane-Type Diterpene Orthoesters and their Biological Activities

“…Since C-1 is the β-carbon of an enone system, a Michael addition might be involved, but the nature of the formal subterminal (terminal) anion equivalent from the acyl moiety is obscure. Furthermore, treatment of daphnane derivatives with npropanethiol failed to afford any 1,2-Michael adduct, despite the high reactivity of thiols in this type of reactions [14].…”

“…The rather broad tolerance of acyl group at C-12 suggests that this moiety essentially acts as an activity modulator, presumably involved in cell penetration but not directly in binding [29,52]. A structure-activity study showed that the acyl moiety at C-12, 5,20-diol system, and the double bond on ring A are all important for the activity, while the 15-double bond is not [14].…”

“…Analogues of mezerein modified on both the 12-acyl and the orthoester moiety are known (12)(13)(14)(15). Among them, gnidiladin (13), also known as odoracin [53] and yuanhuacine [54][55], show nematicidal [53] and antifertility properties [18,56].…”

“…Related compounds isolated from D. genkwa (Yuan Hua of the traditional Chinese medicine) [54,[57][58][59][60][61][62]81] and D. tangutica [18] were studied in China as abortifacients [56,63]. Structure-activity studies showed that esterification of the 20-hydroxyl with fatty acids led to a substantial retention of activity with an overall decrease of toxicity, while formation of an acetonide between the 5-and 20-hydroxyl was detrimental for the activity [56], as also noticed in the cytotoxicity studies [14]. Saturation of the 1,2-double has been reported to occur in the natural products yuanhuatine (52) and yuanhuapine (53) from D. genkwa, which showed a decreased but still significant level of abortifacient activity compared to their unsaturated analogues [56,[64][65].…”