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

为了从海洋生物中寻找新的有药用价值的物质，我们在新的实用生物测定方法的指导下，对从海洋无脊椎动物中分离的生物活性物质进行了化学研究。a）抗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），分离自海洋海绵Haliclona sp.，在神经母细胞瘤细胞系Neuro 2A中诱导神经元细胞分化。LB-A可将Neuro 2A细胞周期阻滞于G1期。实现了LB-A的全合成，并以合适的脂肪酸为原料合成了几种类似物。构效关系研究表明，碳链长度和3R构型对神经突活性有重要影响。为了鉴定LB-A的靶蛋白，我们合成了一种放射性光亲和探针，并成功地进行了原位光亲和标记。 ...更多信息 检测到Mr为30 kDa的蛋白质。2)倍半萜氨基醌（smenospongine）：一种新的倍半萜氨基醌，5-epi-smenospongorine，以及九种已知的倍半萜醌/酚，从海洋海绵Dacquillusspongia elegans中分离出来，作为诱导K562细胞分化成成红细胞的物质。Smenospongine增加K562细胞血红蛋白的产生，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阐明了醌骨架是必不可少的，氨基起着重要的作用。B）抗肿瘤药物多药耐药性的调节剂（P-gp抑制剂）：Kendarimide A是一种新的P-糖蛋白（P-gp）介导的肿瘤细胞多药耐药（MDR）调节剂，其化学结构为N-甲基焦谷氨酸（N-methylpyroglutamic acid，N-PG）的线性肽（pyroMeGlu）、N-甲基化的八元半胱氨酰-半胱氨酸（ox-[MeCys-MeCys]）以及许多N-甲基氨基酸残基，并且通过与合成的模型化合物比较来确定绝对立体结构。少

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