P-25 抗腫瘍性ステロイドサポニンOSW-1類似化合物の立体選択的合成と活性評価(ポスター発表の部)

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OSW-1 is an extraordinarily potent antitumor saponin characterized as a cholestane disaccharide, which has been isolated as a main constituent from the bulbs of Ornithogalum saundersiae. The key characteristics of this series of natural products are their antitumor activity, being over ten times more potent than the clinically used anticancer agents, and the remarkable similarity of the cytotoxicity profile to that of cephalostatins. These attractive bioactivities and the structural novelty have prompted synthetic and bioorganic chemists to perform total and partial synthetic studies of OSW-1. However, researches aiming at the development of new practical anticancer drugs based on OSW-1 have been quite limited, in spite of the necessity of an appropriate drug design to improve the selective cytotoxicity. In this study, we designed three simplified steroidal aglycons, including A-aromatic type (A), A-nor-B-aromatic type (B), and des-AB type (C), as a potential surrogate of the natural OSW-1 aglycon to improve the selectivity and practicality of OSW-1-based antitumor agents. Thus, we started the study on stereoselective syntheses of these target compounds involving their biological evaluation. For the synthesis of the A-aromatic type of aglycon (A), the commercially available estrone (1) was used as a starting material, and introduction of the suitable side chain and installation of the trans-diol unit were performed according to Scheme 1, to accomplish the synthesis in nine steps. The aglycon thus obtained was subsequently subjected to glycosylation with disaccharide found in the natural OSW-1 to produce a new OSW-1 analogue (6, Scheme 2). Evaluation of the bioactivity of this compound revealed that the antitumor activities still stood comparison with those of cisplatin, a clinically used anticancer agent, although being somewhat lower than those of natural OSW-1 itself. These results indicate that the structural modification of the aglycon part can be a useful approach for a discovery of new efficient anticancer drugs. For the synthesis of the A-nor-B-aromatic aglycon (B), a highly stereoselective intramolecular Diels-Alder reaction of o-quinodimethane was utilized as a key step (Scheme 4). The substrates (13) for the thermal reaction were efficiently synthesized from the simple benzocyclobutene derivatives (7) through the seven-step transformations depicted in Scheme 3. The A-nor steroidal ketones (15) were obtained with a high optical purity, which were further transformed into the target aglycon (B) in satisfactory yields. The last target compound, the des-AB type of aglycon (C), was synthesized according to Scheme 5. An optically pure Hajos ketone (16) was converted to a trans-fused bicyclic compound (19) in six steps with a high stereoselectivity, which was successfully transformed into the aglycon (C) via the analogous pathway to that used in the syntheses of the aglycons A and B. Thus, we have accomplished the syntheses of three simplified aglycon of OSW-1, which can be new candidates for anticancer drugs. Further modifications and detailed investigation of the bioactivity are now in progress.
天然有機化合物討論会の論文
2005-09-15

P-25 抗腫瘍性ステロイドサポニンOSW-1類似化合物の立体選択的合成と活性評価(ポスター発表の部)

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