Pharmacological and Biological Studies

Hirono, H. Mori, M. Haga, M. Fujii, K. Yamada, Y. Hirata, H. Takanashi, E. Uchida, S. Hosaka, I. Ueno, T. Matsushima, K. Umezawa, and A. Shirai, Proc. Int. Symp. Princess Tatematsu Cancer Res. Fund, 1979, 79 (Chem. Abstr., 1980, 93, 180 283). 

Kuhara, H. Takanashi, I. Hirono, T. Furuya, and Y. Asada, Cancer Lett., 1980, 10, 117. 

Many pyrrolizidine alkaloids are metabolized to toxic pyrrole metabolites in the liver by mixed-function oxidases. The structural and chemical features necessary for the formation of these metabolites have been discussed.77 The most important features, in addition to the 3-hydroxymethyl-3-pyrroline system, are steric hindrance to hydrolysis of the ester, lipophilic character (favouring attack by the hepatic microsomal enzymes), and the presence of a conformation that allows preferential oxidation of the pyrroline ring rather than 7V-oxidation. The alkylating activities of a series of these pyrrole derivatives have been examined.78 

The effects of pyrrolizidine alkaloids on the mixed-function oxidase enzyme system in rat liver have been studied.79,80 Dehydroheliotridine and heliotrine (at higher dose rates) have similar effects on pregnant rats and their embryos.81 The development of pulmonary hypertension and obstructive lesions in rats after administration of monocrotaline (48) has been studied.82 Butylated hydroxyanisole protects young mice against the acute toxicity of monocrotaline.83 Reduced levels of pyrrole metabolites were observed. 

Tritium-labelled 7V-(4-phenylphenacyl)heliotridanium bromide (55) has been prepared. The absorption, tissue distribution, and excretion of this radioactive antispasmodic drug in rats were then studied.84 

Mattocks has reviewed the metabolic activation of pyrrolizidine alkaloids. Schoen-taP has amplified her hypothesis that the acute effects of pyrrolizidine alkaloid toxidty are due to the alkylation of coenzymes. A summary of the physiological activity and biosynthesis of the pyrrolizidine alkaloids has appeared.  

The pulmonary oedema produced in rats by dehydromonocrotaline has been studied by electron microscopy. Tritiated dehydroretronecine has been used in studies of the binding of this metabolite to macromolecules. Studies in vivo with rhesus monkeys revealed preferential binding of dehydroretronedne to the protein of gastric mucosa. Much less radioactivity was found associated with RNA and DNA. Binding in vitro to calf thymus DNA and bovine serum albumin took place most readily under acidic conditions. Tritiated dehydroheliotridine has been used to study the preferential depression of satellite DNA synthesis by this metabolite in cultured sheep lymphocytes and ovine kidney cells. The mechanism of the antimitotic action of lasiocarpine and dehydroheliotridine has been investigated in 

Mattocks, Proc. 11th Internat. Cancer Congr. , Florence, 1974, Excerpta Med. Internat. Congr. Ser. No. 350, Excerpta Medica, Amsterdam, 1975, Vol. 2, Chem. Viral Oncogenesis, p. 20. 

The complex relationship between certain genera of butterflies belonging to the nymphalid subfamilies Danainae and Ithomiinae, and pyrrolizidine alkaloid containing plants has been discussed. As well as using alkaloids as precursors of pheromones, male butterflies are believed to use pyrrolizidine alkaloids to produce compounds used for territory marking (see above). 

Mortimer and E. P. White, Proc. New Zealand Weed Control Conf., 1975, 28, 88. 

Two outbreaks of human liver disease in India have been attributed to the consumption of plants containing pyrrolizidine alkaloids. In the first instance, the disease was caused by eating cereals contaminated with seeds of a Crotalaria species.56 Haemodynamic studies were carried out on eight patients suffering from the characteristic veno-occlusive disease. In the second study, two cases of sudden liver failure that are believed to be due to the ingestion of herbal concoctions made from seeds and plants of Heliotropium species are reviewed.57 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Collagen synthesis increased in the pulmonary arteries of rats which had been treated with monocrotaline.70 Doronine has an hypotensive effect when administered to cats.71 Senecionine and otosenine showed spasmolytic activity on the intestinal smooth muscles of mice.72 

Some semi-synthetic quaternary pyrrolizidine derivatives have marked biological activities. Ganglion- and neuromuscular-blocking activities were 

The health hazards of pyrrolizidine alkaloids have been reviewed. 

Indicine N-oxide (49) is an antitumour agent which is being used 

The diastereoisomeric N-oxides (50) have been prepared from (+)-retronecine (1) and ( )-2-hydroxy-2-phenylbutanoic acid,using N,N -carbonyldiimidazole as the coupling reagent (c. Vol. 8, p. 48). This diastereoisomeric mixture is a more active anti- 

A series of quaternary ammonium derivatives of 9-thioretro-necine have been made, and (51) was the most effective on blocking 

Pyrrolizidine alkaloids may be present in some traditional herbs used in Sri Lanka, and this may account for the high incidence of chronic liver disease in this country. Chinese workers are becoming interested in the structure-activity relationships of 

The seed mortality due to chewing insects is high for the East African population of the shrub Crotalaria pallida. Unexpectedly, it was found that plants with higher levels of alkaloid in the seeds experienced greater seed predation. 

All 27 bisquaternary derivatives of pyrrolizidine alkaloids tested inhibited nerve muscle transmissions. One of the most active compounds studied was nonamethylene-l,9-bisviridiflorium dibromide (57). 

The known alkaloids ( )-elaeocarpine and ( )-isoelaeocarpine, and a new alkaloid rudrakine, C16H23NO3, have been isolated from leaves of Elaeocarpus ganitrus. Rudrakine is a minor component, and, mainly from mass spectroscopic data, it has been given structure (1), without any assignment of relative stereochemistry.  

A further synthetic route to Elaeocarpus alkaloids has been explored. Acylation of the lithium enolate of 7-oxoindolizidine (2) by 2-methoxy-6-methyl-benzoyl cyanide (3) gave the diketone (4), which is a key intermediate in a previously reported synthesis of elaeocarpine. 

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Despite the existence of a large number of taxol derivatives, only taxol itself has given rise at present to significant pharmacological and biological studies. However, some work employing the mixture taxol—cephalomannine 115) (more easily extracted from the bark of T. baccata than taxol itself) as well as derivatives having a xylose residue attached to the taxane skeleton may be cited 116). 

Structure-activity relationships evolved from the assumption that the structure of a molecule is related in some way to its biological activity. Such relationships have been the bacldwne of numerous pharmacological and toxicological studies for many years. It is not surpdsing that the field of pharmaceutical science has lead to the identification and implementation of new techniques, to aid in defining structure-activity relationships. 

Pharmacological and metabolic studies on cannabinoids (Fig. 1) have suffered from a lack of knowledge of their physico-chemical properties and the insensitivity of assays of A -tetrahydrocannabinol 1, and its metabolites in biological fluids. Unambiguous, sensitive, specific and accurate quantification is required for forensic toxicology and pharmacokinetic studies which can be correlated with the time course of the psychoactive effects (2). 

The BLA must describe all nonclinical pharmacology and toxicology studies conducted on the biologic product. These nonclinical laboratory studies include those submitted in the IND, those submitted during clinical investigations, and new nonclinical studies not previously submitted. The Center for Biologies Evaluation and Research reviews these studies to evaluate their adequacy and comprehensiveness and to ensure that there are no inconsistencies or inadequately characterized toxic effects. The application also should include information on studies not performed by the sponsor but of which the sponsor has become aware (e.g., studies in published literature). 

Because of the potentially useful pharmacological and biological applications of phenothiazine derivatives, it is very important to investigate the physicochemical aspects of their interactions and aggregations within organized media, such as CDs and micelles of surfactants. As a consequence, several literature studies have been reported in this field [35-44],... 

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