Search for New Anti-Cancer Seeds Targeting for cell Differentiation and cell Cycle

寻找针对细胞分化和细胞周期的新抗癌种子

• 批准号: 13470470
• 负责人: KOBAYASI Motomasa
• 金额: $ 8.77万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470470/
• 关键词: Indonesia; Marine sponge; Cell differentiation; Anti-tumor; Biological active; cell cycle

In search of new anti-cancer substance from marine organisms, we have constructed the following four bioassay systems and screened the extracts of the marine sponges, which we have collected in the fields.(1) Search for differentiation inducer against K562 cells to erythrocyte or macrophage(2) search for inducer of neuronal differentiation against neuroblastoma Neuro 2A cells(3) search for inducer against ras-transformed cells to normal cell(4) search for selective inhibitor of cell cycle. we have screened about 400 extracts of marine sponges, and the active extracts were further subjected to fractionation and isolation on the guidance of the above bioassay systems. The results summarize as follows.1. As for the neuritogenic long-chain polyketide, lembehyne A, we achieved the first total synthesis. Further analong synthesis of lembehyne A and structure-activity relationship study clarified that 3R-hydroxy-1-yen structure and proper length of long-chain play a important role for neurito … More genic activity of lembehyne A. Lembehyne A induced increase of cycline-dependent kinase P21 and arrested cell cycle of Neuro 2A cell at the G1 phase and also esterase. In order to elucidate target protein of lembehyne A, we designed and synthesized a radioactive photoaffinity probe of lembehyne A.2. An alkaloid, hymenialdisine, isolated from Indonesian marine sponge induced differentiation of K562 cells to macrophage. Hymenialdisine induced morphological changes, G2/M arrest of cell cycle, reduction of NBT, and increase of acetylcholine esterase against K562 cells. Hymenialdisine also inhibited CDK1/cvcB complex, which might be one of target protein.3. Pyridoacridine alkaloids isolated from Indonesian marine sponge induced neuritogenesis against Neuro 2A cell and increase of acetylcholine esterase lebel and arresed cell cycle at the G2/M phase.4. A novel anthracycline, komodoquinone A, isolated from the solid-state fermentation of streptomyces sp. Induced differentiation and G1 arrest against Neuro 2A cells. Less

为了从海洋生物中寻找新的抗癌物质，我们构建了以下四个生物测定系统，并筛选了我们在野外采集的海绵提取物。(1)寻找抗K562细胞向红细胞或巨噬细胞分化的诱导剂（2）寻找抗神经母细胞瘤Neuro 2A细胞的神经元分化的诱导剂（3）寻找抗ras转化细胞向正常细胞分化的诱导剂（4）寻找细胞周期的选择性抑制剂。我们筛选了约400种海绵提取物，并在上述生物测定系统的指导下对活性提取物进行了进一步的分级分离。研究结果如下：1.至于神经元长链聚酮，lembehyne A，我们实现了第一个全合成。通过对Lembehyne A的合成及构效关系的研究，阐明了3R-羟基-1-苯基结构和合适的长链长度对神经毒素的作用 ...更多信息 Lembehyne A. Lembehyne A可诱导细胞周期蛋白依赖性激酶P21的表达增加，并使细胞周期阻滞于G1期，同时还可诱导酯酶活性的增加。为了阐明lembehyne A的靶蛋白，我们设计并合成了lembehyne A的放射性光亲和探针。从印度尼西亚海绵中分离的生物碱，海美纳地辛，诱导K562细胞向巨噬细胞分化。Hymenialdisine可诱导K562细胞形态学改变、细胞周期G2/M期阻滞、NBT含量降低和乙酰胆碱酯酶活性升高。Hymenialdisine对CDK 1/cvcB复合物也有抑制作用，该复合物可能是靶蛋白之一.从印尼海绵中分离的吡啶并吖啶类生物碱能诱导Neuro 2A细胞的神经突形成，增加乙酰胆碱酯酶活性，并使细胞周期阻滞于G2/M期.从链霉菌固态发酵中分离的一种新型蒽环类抗生素科莫多醌A对Neuro 2A细胞诱导分化和G1期阻滞。少

项目成果

Aoki S, Naka Y, Itoh T, Furukawa T, Rachmat R, Akiyama S, Kobayashi M: "Lembehsterols A and B, novel sulfated sterols inhibiting thymidine phosphorylase, from the marine sponge Petrosia strongylata"CHEMICAL & PHARMACEUTICAL BULLETIN. 50(6). 827-830 (2002)

Aoki S、Naka Y、Itoh T、Furukawa T、Rachmat R、Akiyama S、Kobayashi M：“Lembehsterols A 和 B，抑制胸苷磷酸化酶的新型硫酸化甾醇，来自海洋海绵 Petrosiastrongylata”化学

M.Kobayashi: "N.Fusetani(ed.) Drugs from the sea, Basel, Karger"Search for biologically active substances from marine sponges. 46-58 (2000)

M.Kobayashi：“N.Fusetani（编）来自海洋的药物，巴塞尔，Karger”从海绵中寻找生物活性物质。

S.Aoki: "Lembehyne A, a spongean polyacetylene, induces neuronal differentiation in neuroblastoma cell"Biochem.Biophys.Res.Commun.. 289. 558-563 (2001)

S.Aoki：“Lembehyne A，一种海绵聚乙炔，诱导神经母细胞瘤细胞中的神经元分化”Biochem.Biophys.Res.Commun.. 289. 558-563 (2001)

S.Aoki: "Reversing effect of agosterol A, a spongean sterol acetate, on multidrug resistance in human carcinoma cells"Jpn.J.Cancer Res.. 92. 886-895 (2001)

S.Aoki：“阿戈甾醇 A（一种海绵甾醇乙酸酯）对人类癌细胞多药耐药性的逆转作用”Jpn.J.Cancer Res.. 92. 886-895 (2001)

Ozaki H, Hori M, Kim YS, Kwon SC, Ahn DS, Nakazawa H, Kobayashi M, Karaki H: "Inhibitory mechanism of xestosponign-C on contraction and ion channels in the intestinal smooth muscle"BRITISH JOURNAL OF PHARMACOLOGY. 137(8). 1207-1211 (2002)

Ozaki H、Hori M、Kim YS、Kwon SC、Ahn DS、Nakazawa H、Kobayashi M、Karaki H：“xestosponign-C 对肠平滑肌收缩和离子通道的抑制机制”英国药理学杂志。