38 アポトーシス抑制タンパク質Bcl-2の機能を克服する新規物質インセドニンの発見・構造解析・生物活性(口頭発表の部)

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It is well known that the anti-apoptotic protein Bcl-2 and its homologue Bcl-X_L are overexpressed in many human cancers and play a crucial role in cancer progression. Therefore, the functional blockade of Bcl-2/Bcl-X_L will be a promise for novel anticancer therapeutics by way of improving tumorigenesis. In the course of screening for an inhibitor of Bcl-X_L, anti-apoptotic function using human SCLC Ms-1 cells that overexpress Bcl-X_L, we found Incednine (1) in the fermentation broth of the strain Streptomyces sp. ML694-90F3. 1 was isolated as a HCl salt by using the Centrifugal liquid-liquid Partition Chromatography, effectively. The planar structure of 1, C_<42>H_<63>N_3O_8 ([M+H]^+, m/z 738.4680, Δ-1.3mmu), was elucidated on the basis of the various NMR spectra data including TOCSY experiments (Fig. 1). The relative stereochemistry of 1 was determined by the analysis of NOE experiments and coupling constants (Fig. 2). The conformation of the aglycon was confirmed by Discovery III-computations. The absolute stereochemistry of 1 was established by modified Mosher's method and X-ray crystallographic analysis (Fig. 3, 4). Incednine has a unique skeletal structure, "enol-ether amide" in the 24-membered macrolactum core, with an attachment of a disaccharide. Bcl-X_L-overexpressing Ms-1 cells displayed resistance to several anti-tumor agents, however, anti-tumor agents-induced cell death was observed only when cells were treated with 1. Overexpression of Bcl-X_L inhibited cell death in Bax-overexpressing HEK293T cells by forming a complex with Bcl-X_L and Bax, whereas it failed to inhibit cell death in the presence of 1 without affecting the formation of Bcl-X_L and Bax complex. The inhibitory mechanism of anti-apoptotic Bcl-X_L by 1 is now under investigation.
天然有機化合物討論会の論文
2005-09-15

38 アポトーシス抑制タンパク質Bcl-2の機能を克服する新規物質インセドニンの発見・構造解析・生物活性(口頭発表の部)

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