Alkaloids structure-toxicity relationship

A number of studies of the pharmacology and toxicology of the diterpenoid alkaloids have appeared.These will not be reviewed, but are cited for reference. Of particular interest is a review of the toxicity data and structure-toxicity relationships for Cl 9- and C20 alkaloids of Aconitum species. 

Roder et al. [36] and Hille [85] detected the pyrrolizidine alkaloids tussilagin and isotussilagin in . purpurea roots and reported a content of 0.006% tussilagin for the dried drug. According to the structure-toxicity relationships elucidated by Mattocks [38], a 1,2-unsaturated necine ring system is necessary for the hepatotoxicity... 

In this chapter, a rationale of the structure-activity relationships of various series of bioactive secondary metabolites from Indo-Pacific marine invertebrates is reviewed. These include alkaloids, terpenes and polybrominated diphenyl ethers which were subjected to a series of bioassays in search for insecticidal, antibacterial, fungicidal, and cytotoxic lead compounds. From these various biotests, it was observed that the bioactivity of an analogue is not due to general toxicity but rather possesses a degree of specificity on a particular target biomolecule. The relationship between chemical structures and biological activity is related to the specific action of a compound. 

As a result of these studies we have isolated bioactive compounds belonging to several chemical classes (sesquiterpenes, diterpenes, lignans, diterpenoid alkaloids, pyrrolizidine alkaloids) with selective modes of action and low toxicity. The structure-activity relationships of these compounds have also been established. 

Structure Activity Relationship. Attempts to relate alkaloid structure to toxicity have been based on studies with rats in which single doses of alkaloids were administered via intraperi-toneal or intravenous injection. The objective of the early studies was establishment of median lethal doses (LD50) based on... 

In the examination of the toxic tall larkspurs, several adjustments of the research approach were necessary to develop an efficient research plan. First, the etiology of tall larkspur poisoning is well established and several species of tall larkspur are clearly recognized as threats to livestock. Furthermore, research information exists on the isolation of toxic components from both Aconitum and Delphinium species and on the toxicity, structure/activity relationships and mode of action of the alkaloids obtained from toxic larkspurs (see previous discussion). Less information is available about toxins present in the... 

Manners, G. D., Panter, K. E., and Pelletier, S. W. 1995. Structure-Activity Relationships of Norditerpenoid Alkaloids Occurring in Toxic Larkspur Delphinium) Species. Journal of Natural Products 58 863-869. 

VRLB is a semisynthetic derivative ofVLB (5 -noranhydrovinblastine), structurally distinguished from other members of its class by the modification of the cathar-anthine nucleus rather than the vindoline ring. This alteration is probably responsible for differences in its antitumor activity and tolerability profile compared with other vinca alkaloids [68]. VRLB is effective as monotherapy or in combination with a platinum derivative in patients with advanced NSCLC and advanced breast cancer [69,70]. Myelosuppression is the major dose-limiting toxicity. VRLB is administered weekly nadirs are usually reached within 14 days and patients recover within the next two weeks [71]. VRLB is also well absorbed orally. Oral and i.v. forms show similar interindividual variability, the same metabolism pattern, reproducible intrapatient blood exposure, and the same pharmacokinetic-pharmacodynamic relationship. Given at 60 mg/m /week for the first three administrations and then increased to 80 mg/m /week it achieved the same efficacy as i.v. VRLB (30 mg/m ) in terms of progression-free survival, overall survival, and objective response [70]. 

Heteratisine.—A detailed report on the chemical elucidation of the structure and stereochemistry of heteratisine (19) has appeared. This lactone diterpenoid alkaloid has been isolated along with its monobenzoyl ester from the roots of Aconitum heterophyllum Wall. Heteratisine has not been detected in any other plant. An earlier 2f-ray crystallographic analysis of the hydrobromide monohydrate of heteratisine indicated the identical structure. Heteratisine thus bears a closer structural relationship to the highly toxic and polyoxygenated alkaloids of the lycoctonine-aconitine type than to its companion bases atisine, atidine, and hetisine. 

Elbein and Molyneux (36) in an earlier review emphasized that three structural features are common in all alkaloid glycosidase inhibitors (AGI) which are toxic to mammals they have a secondary or tertiary nitrogen atom in a pyrrolidine, piperidine or indolizidine ring they have at least three hydroxyl groups in a jS-position relative to the nitrogen and they have fixed stereochemical relationships between the hydroxyl groups, which likely accounts for the specificity of the enzyme inhibition observed. Data from insect studies suggest that these same structural constraints may apply. Clearly there is much yet to be learned empirically about specificity of these compounds. 

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