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1 Wiadomości Chemiczne

1 2001

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Nowe produkty naturalne o działaniu cytostatycznym

Gryszkiewicz A., Jastrzębska I., Morzycki J.W.

Wiadomości Chemiczne

2001

[Z] 55, 9-10

793-820

Secondary metabolites of marine invertebrates continue to attract attention of organic chemists, biochemists, and pharmacologists due to their interesting structures and potent biological activities. One such example is cephalostatin 1 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi, which exhibited remarkable cytotoxic activity against a broad spectrum of malignant tumor cells. Similar marine alkaloids were found in the lipophilic extract of the tunicate Ritterella tokioka collected off the coast of Japan. These very potent compounds, cephalostatins and ritterazines, belong to the large family of trisdecacyclic pyrazines consisting of two steroid units. The two steroid halves of cephalostatin 1 and other highly cytotoxic members of the family are different. The biological activity of the dimeric steroid-pyrazine marine alkaloids and their limited availability coupled with the new and intriguing structure make them an attractive challenge for the synthetic organic chemists. A few years ago a group of cholestane glycosides was isolated from the bulbs of Ornithogalum saundersiae, a species of the lily family without any medicinal folkloric background. The major component of the mixture of saponins, OSW-1, exhibited sub-nanomolar antineoplastic activity. While OSW-1 is exceptionally cytotoxic against various tumor cells, it showed little toxicity to normal human pulmonary cells. The cytotoxicity profile of OSW-1 against different cancer cell lines was found to be surprisingly similar to that of the cephalostatins, which appears to imply a related mechanism of action [36]. In this review article the synthetic efforts towards these compounds are described. One of the key features of any attempted synthesis of bis-steroidal pyrazines is the central heterocyclic ring. The classical method of pyrazine synthesis involves the dimerization of a-amino ketones. An obvious disadvantage of a-amino ketones dimerizations is their unsuitability for unsymmetrical cross-coupling. Various methods for preparation of unsymmetrical pyrazines were developed. However, the preparation of suitably functionalized steroid units is still an uphill challenge, although a significant progress in this endeavor was achieved. This is exemplified among others by the synthesis of cephalostatin 1. The highly active "interphylal" hybrid analogues, ritterostatins and ornithostatins, were also obtained. Since saponin OSW-1 contains a relatively simple steroid skeleton, it is an attractive synthetic goal. The synthesis of the OSW-1 aglycone, and later the saponin OSW-1, was successfully accomplished. The mode of action of OSW-1 and of the cephalostatin family is not known yet, but it seems that an oxocarbenium ion, which could be generated from both types of compounds, is the likely intermediate responsible for their cytotoxicity.