32 新規神経突起伸長阻害物質インドカルバゾスタチン類の構造と活性(口頭発表の部)

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During the course of screening for modulators of signal transduction of mammalian cells, we have discovered two novel inhibitors, indocarbazostatin (1) and indocarbazostatin B (2) from a culture broth of a Streptomyces sp. (Fig. 1). In our assay system, 1 inhibited NGF-induced neurite outgrowth from PC12 cells at 6nM, which is approximately 33 times higher than that of K252a. We would like to present structures, biological activities and some biosynthetic aspect of these natural products during this symposium. Among 4671 extracts, only one culture produced active compounds of interest. The producing strain identified as Streptomyces sp. TA-0403 was cultivated at 30℃ for 3 days in 500mL cylindrical flasks each containing 70mL of the medium. The fermentation broth (35L) was centrifuged and the mycelial cake was extracted with acetone. After the removal of acetone, pure compounds 1 and 2 were isolated as shown in Scheme 1. The HR FAB-MS, UV, ^1H and ^<13>C NMR data indicate the chromophore system of these compounds to be hetero-atom substituted indolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7(6H)-dione. The structure of 1 was deduced from ^1H-^1H COSY, PFG HMBC, PFG HMQC, and DIF NOE data. The NMR assignments for 1 are summarized in Table 1. The relative and absolute configurations of the sugar moiety of 1 were clarified by MM2 and MOPAC calculations (Fig. 2) and CD analyses. Also, the structure of 2 was obtained through a similar approach. Thus, the structures of 1 and 2 were determined as shown in Fig. 1. Indocarbazostatin (1) and indocarbazostatin B (2) are new members of indolocarbazole-type bioactive molecules. The compounds 1 and 2 inhibited NGF-induced neurite outgrowth from PC12 cells at 6nM and 24nM respectively, whereas K252a inhibited at 200nM under our assay conditions (Fig. 3). K252a showed cytotoxicity at a concentration three times higher than the minimal effective concentration. However, 1 did not show obvious cytotoxicity to PC12 cells at a concentration nine times higher than the minimal effective concentration. The IC_<50> values for PKC were: 1 2.0nM, 2 8.5nM and K252a 35nM. The enhancement of productivity of 1 and 2 by UV radiation rearing of the producing strain, and their biosynthetic studies will be discussed in the symposium also.
天然有機化合物討論会の論文
2000-10-01

32 新規神経突起伸長阻害物質インドカルバゾスタチン類の構造と活性(口頭発表の部)

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