P-34 光学活性デュオカルマイシンAおよびその類縁体の合成と抗腫瘍活性(ポスター発表の部)

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Duocarmycins (1-6) isolated from Streptomyces sp. are novel antitumor antibiotics which are effective against various types of murine cancers. Synthesis of optically active (+)-1, (-)-1, and their C2-epimers (2-epiduocarmycin A) [(+)-7 and (-)-7] was examined to explore the relationships between absolute configuration and cytotoxicity. These studies let us develop novel duocarmycin congeners showing prominent antitumor activity. Thus, the optical resolution of tricyclic alcohols (dl-15 and dl-16) was achieved by separating their (S)-O-acetylmandelic esters by HPLC. After removal of the (S)-P-acetylmandelic acid moiety, the optically active alcohols (15^* and 16^*) were elaborated to optically active (+)-1, (-)-1, (+)-7 and (-)-7, respectively, in the same manner as employed for the synthesis of racemates. The absolute configurations of synthetic (+)-1 and (-)-1 were established by comparing their optical rotation values with that of natural (+)-1. Determination of the absolute configurations of unnatural (+)-7 and (-)-7 was next attempted by the optical resolution of the isatin derivative (dl-12) carrying a single asymmetric center. After experimentation, we found that the diastereomeric esters (19/ and 19m) prepared from dl-12 and the novel resolving agent, (S)-N-cinnnamoylproline, can be readily separated by column chromatography. The less polar ester (19/)was derived to the mandelates (17/ and 18/), by way of 15^* and 16^*. Based on these experiments correlating (+)-1 and (+)-7, the absolute configurations of (+)-7 and (-)-7 were definitely determined. With (+)-1, (-)-1, (+)-7 and (-)-7 in hand, their in vitro cytotoxicity against P388 murine leukemia was next studied. It was found that the level of cytotoxicity highly depends upon the absolute configuration of cyclopropane moiety and not upon that at the C2-position. In order to improve efficiency for producing (+)-1, (+)-7, and their congeners, we next examined the optical resolution of racemic bicyclic intermediate (dl-21) at the early synthetic stage. After numerous attempts, it was found that the diastereomeric (S)-N-cinnamoylprolyl esters (22/ and 22m) derived from dl-21 can be cleanly separated by a single recrystallization, affording less polar 22/ as crystals. This was elaborated to optically active key intermediate [(+)-11] with high optical purity. The more polar isomer (22m) was readily recycled to dl-21 by way of exomethylene derivative (25). Next, with an aim to prepare more effective anticancer agents, an efficient synthetic method was sought which can construct a novel pyrroloindole ring system such as those involved in dl-26. After experimentation, we found that pyrroloindole derivatives (dl-28) can be effectively produced from enamino esters (dl-28) by oxidative cyclization using palladium acetate. Subsequent chemical operations including condensation with various carboxylic acids furnished duocarmycin congeners (dl-27). These congeners were subjected to in vitro cytotoxicity and in vivo antitumor activity assay against P388 murine leukemia. Among dl-27 tested, those carrying a trifluoromethyl group (dl-27b) were found to exhibit promising in vitro and in vivo activity. Some of optically active duocarmycin congeners (27b^*) were similarly prepared by employing readily available (+)-11.
天然有機化合物討論会の論文
1994-09-20

P-34 光学活性デュオカルマイシンAおよびその類縁体の合成と抗腫瘍活性(ポスター発表の部)

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