Indicine N-oxide

The Borage plant (syn. Forget-me-not) family (Boraginaceae Lindl.) contains L-ornithine (Figure 11 and 15) derived alkaloids, such as indicine-N-oxide in the heliotrope (Heliotropium indicum) and southern hound s tongue Cynoglosum creticum) species (Table 8). Farsam et al. reported on new alkaloids from... 

Powis, G., Ames, M. M. and Kovach, J. S. 1979. Metabolic conversion of indicine-N-oxide to indicine in rabbits and humans. Cancer Research, 39 3564-3570. 

Cook, B. A., Sinnhuber, J. R., Thomas, R J., Olson, T. A., Silverman, T. A., Jones, R., Whitehead, V. M., and Ruymann, R B. (1983). Hepatic failure secondary to indicine N-oxide toxicity. A Pediatric Oncology Group Study. Cancer 52 61-63. 

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. 

Indicine N-oxide Active against P388 mouse leukemia — 311... 

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

Additional studies have shown that the oxidation of alkaloid to its N-oxide occurs and competes with pyrrole formation. N-oxides when administered intravenously to rats or when treated with liver microsomal enzymes are not converted to pyrroles. Hence they are non-toxic in the liver, and, by their highly hydrophilic nature, provide a pathway for detoxification. When administered orally to rats and sheep however, N-oxides are converted in the rumen (sheep) or gut (rats) to the parent alkaloids which are then metabolized in the liver causing the normal toxic sequelae. The toxicity (or lack thereof) of the pyrrolizidine N-oxides depends on whether or not they are reduced vivo before reaching the liver (61). After intravenous administration of indicine N-oxide to human cancer patients, free alkaloid has been detected in the blood and subsequent liver damage has been observed (55). 

Pyrrolizidine alkaloids Pyrrolizidine Acetyl-lycopsamine Acetyl-intermedine Europine Homospermidine llamine Indicine-N-oxide Meteloidine Retronecine... 

Boraginaceae, Asteraceae, andFabaceae) are the most important sources of these compounds. In Fabaceae, the genus Crotalaria is particularly representative of p5Trolizidine alkaloids, and in Asteraceae, the genus SenecioP The characteristics of these alkaloids are as follows (1) they are accumulated in plants as N-oxides (2) they are poisons (3) some of them have a bioimpact (e.g., indicine-N-oxide). 

Natural products have a history of providing novel, clinically useful anticancer drugs and a number of these have come from higher plants (ref. 1-21). In addition, many of these compounds have served as prototypes for the development of novel analogs of clinical importance. Some specific examples are colchicine (ref. 22) and its derivatives, the podophyllotoxins (ref. 23) including the clinically-effective epipodophyllotoxin derivatives etoposide and teniposide (ref. 24), and the Vinca alkaloids, vincristine, vinblastine, and vindesine (ref. 25,26). More recently indicine N-oxide, homoharringtonine and taxol have entered clinical trials (ref. 13,21). The discovery of natural products with potential as anticancer drugs has recently been reemphasized by the NCI. 

Indicine-N-oxide (97), the enantiomer of the natural antitumour agent, has been prepared by linking the previously... 

A variety of pyrrolizidine alkaloids and their N-oxides have antitumor activity (Wink, 1993b). Herbal material of Senecio vulgaris (Asteraceae) has been used for hundreds of years as a treatment for cancer. The active compounds have been shown to be senecionine (5) and senecionine N-oxide. Indicine N-oxide (16) from Heliotropium indicum (Boraginaceae) has pronounced antitumor activity. Mono-crotaline (8), from several Crotalaria species (Fabaceae), has similar activity (Blasko and Cordell, 1988 Suffness and Cordell, 1985). Alkylation seems to be involved in the antitumor activity. As the A -oxides cannot serve as enamines and hence cannot be directly involved in alkylation, these compounds should only be active to the extent they are converted to the free bases. At least in the case of indicine iV-oxide (16), this does not appear to be the case (Suffness and Cordell, 1985). 

Kovach JS, Ames MM, Powis G, Moertel CG, Hahn RG, Creagan ET (1976) Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine N-oxide. Cancer Res 39 4540-4544... 

Miser JS, Smithson WA, Krivit W, Hughes C, Davis D, Krailo M, Hammond D (1991) Phase 11 trial of indicine N-oxide in relapsed pediatric solid tumors, hivestig N Drugs 9 339-342... 

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