Structure-Activity Relationships of Norditerpenoid Alkaloids Occurring in Toxic Larkspur (Delphinium) Species

Abstract

Fourteen norditerpenoid alkaloids present in larkspur (Delphinium) species associated with cattle poisoning on grazing land in the western United States have been toxicologically assessed in a mouse bioassay. Toxicity data for these alkaloids have established the tertiary nitrogen atom and anthranilic acid esterification as important structural features necessary to impart toxicity to lycoctonine-type norditerpenoid alkaloids. Variation in C-14 functionality of the toxic alkaloids is also a factor that influences toxicity in these compounds. The relationship of the structure-activity information of this study to previous in vitro neuromuscular studies is discussed.

Structure-Analgesic Activity Relationship Studies on the C18- and C19-Diterpenoid Alkaloids

“…N-Deethylcrassicauline A (6), Ndeethylcrassicauline A imine (7) and crassicauline A lactam (8) were achieved by reaction of crassicauline A with N-bromosuccinimide (NBS)-glacial acetic acid based on the methods developed by us. 22,23) Pyrocrassicauline A (19) and 13-tbutoxycarbonyl-pyrocrassicauline A (20) were prepared by selective hydrolysis of crassicauline A with dioxane-H 2 O (2 : 1) according to Murayama's method 4) followed by refluxing with (Boc) 2 O in 41% and 35% yields, respectively. 1,16-Didemethoxy-D 15,16 -yunaconitine (26), 1-demethoxy-3,13-diacetyl-14-methane sulfonyl-pyrobikhaconine (27) were readily prepared according to the method reported in the literature.…”

“…Although there are a few reports 11,13,[17][18][19][20][21] on the structure-analgesic activity relationship studies on the C 18 -and C 19 -diterpenoid alkaloids, further specific information on the structure features necessary for the analgesic activity of these compounds is still needed. In this paper, twenty-five semisynthetic derivatives were prepared from lappaconitine, crassicauline A, and yunaconitine.…”

Adverse Effects of Larkspur (Delphinium spp.) on Cattle

“…Delphinium species contain numerous norditerpenoid alkaloids which represent two structural types the N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type and the non MSAL-type, which includes the 7,8-methylenedioxylycoctonine (MDL)-type alkaloids. Purified alkaloids of these two structural types differ significantly in toxicity based upon an LD50 in a mouse model [9,[13][14][15]. In general, the non MSAL-type alkaloids are 20-30 times less toxic compared to the MSAL-type in the mouse model.…”

“…Therefore, based upon the results of that study, a 500 kg cow should be able to consume up to 1.67 kg of fresh tall larkspur per day without becoming severely poisoned. Due to the fact that the MSAL-type alkaloids are much more toxic than the MDL-type alkaloids [13,14], management recommendations for grazing cattle on larkspur-containing ranges are based primarily on the concentration of MSAL-type alkaloids in larkspur [5,37]. However, in many species of tall larkspur the non MSAL-type alkaloids can be more abundant [7,17].…”

Novel Products from Oxidation of the Norditerpenoid Alkaloid Pseudaconine with HIO4.

“…1b, [2][3][4] In the course of these works, it has been observed that these diterpenoid alkaloids have a propensity to undergo complex reactions in the skeletal core.…”