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Search for inhibitors of cell cycle and development for natural molecular probe

细胞周期抑制剂的寻找及天然分子探针的开发

基本信息

批准号：
15310148
负责人：
KOBAYASHI Motomasa
金额：
$ 9.86万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

In search of new pharmaceutically valuable substances from marine organisms, we have been engaged in chemical studies on the bioactive substances, which was isolated from marine invertebrates on the guidance of new practical bioassay.a)Differentiation inducer against leukemia cells and neuroblastoma1)Long-chain acetylene alcohol (lembehyne A) : Lembehyne A(LB-A), isolated from marine sponge of Haliclona sp., induced neuronal cell differentiation in a neuroblastoma cell line, Neuro 2A. Furthermore, the cell cycle of Neuro 2A cell was found to be specifically blocked at the G1 phase by LB-A. The total synthesis of LB-A was achieved, and the several analogues were synthesized from suitable fatty acids. The structure-activity relationship study revealed that the carbon-chain length and 3R configuration are important for neuritogenic activity. To identify the target protein for LB-A, a radioactive photoaffinity probe was synthesized, and the in situ photoaffinity labeling was succeeded in t … More he detection of a protein of Mr 30 kDa. 2)Sesquiterpene aminoquinone (smenospongine) : A new sesquiterpene aminoquinone, 5-epi-smenospongorine, together with nine known sesquiterpene quinone/phenols, was isolated from the marine sponge Dactylospongia elegans as differentiation-inducing substances to K562 cells into erythroblast. Smenospongine increased hemoglobin production in K562 cells and showed increase of glycophorin A expression. The structure-activity relationship study of these compounds clarified that the quinone skeleton is indispensable and the amino group plays an important role.b)Modulator of multi-drug resistance against anti-tumor drugs (inhibitor of P-gp) :Kendarimide A, a novel modulator of multi-drug resistance(MDR) in tumor cells mediated by P-glycoprotein(P-gp) was isolated from a marine sponge of Haliclona sp. The chemical structure of kendarimide A was characterized to be a linear peptide composed of N-methylpyroglutamic acid (pyroMeGlu), N-methylated eight-membered cysteinyl-cysteine (ox-[MeCys-MeCys]) together with many N-methyl amino acid residues, and the absolute stereostructure was determined by comparison with synthetic model compounds. Less

为了从海洋生物中寻找新的药用价值物质，我们在新的实用生物测定的指导下，对从海洋无脊椎动物中分离出的生物活性物质进行了化学研究。a)针对白血病细胞和神经母细胞瘤的分化诱导剂1)长链乙炔醇（lembehyne A）：Lembehyne A（LB-A），从海洋中分离 Haliclona sp. 的海绵诱导神经母细胞瘤细胞系 Neuro 2A 中的神经元细胞分化。此外，发现Neuro 2A细胞的细胞周期被LB-A特异性阻断在G1期。实现了LB-A的全合成，并由合适的脂肪酸合成了几种类似物。结构-活性关系研究表明，碳链长度和3R构型对于神经突活性很重要。为了鉴定LB-A的靶蛋白，合成了放射性光亲和探针，并通过原位光亲和标记成功检测到了Mr 30 kDa的蛋白。 2）倍半萜氨基醌（smenospongorine）：从海洋海绵Dactylospongia elegans中分离出一种新的倍半萜氨基醌，5-表-smenospongorine，以及九种已知的倍半萜醌/酚，作为K562细胞向红细胞分化的诱导物质。 Smenospongin 增加 K562 细胞中血红蛋白的产生，并显示血型糖蛋白 A 表达的增加。这些化合物的构效关系研究表明，醌骨架是不可或缺的，氨基起着重要作用。b)抗肿瘤药物多药耐药调节剂（P-gp抑制剂）：Kendarimide A是从海洋生物中分离得到的一种新型P-糖蛋白（P-gp）介导的肿瘤细胞多药耐药（MDR）调节剂。 Haliclona sp. 海绵Kendarimide A的化学结构被表征为由N-甲基焦谷氨酸（pyroMeGlu）、N-甲基化八元半胱氨酰-半胱氨酸（ox-[MeCys-MeCys]）和许多N-甲基氨基酸残基组成的线性肽，并通过与合成的模型化合物比较确定了其绝对立体结构。较少的