Development of New Anticancer Agents with New Pharmacological Mechanism

具有新药理机制的新型抗癌药物的开发

• 批准号: 11672118
• 负责人: MIKAMI Yoshihiro
• 金额: $ 1.73万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672118/
• 关键词: OSW-1; steroidal glycoside; steroidal saponin; HL-60 cells; cytotoxic activity; antitumor activity; structure-activity relationship; anticancer agent; Ornithogalum thyrsoides; Galtonia candicans; candicanoside A; パネルスクリーニング; galtonioside A; 細

Previously, we have found that an acylated cholestane glycoside (XDSW-1) isolated from the bulbs of Ornithogalum saundersiae showed potent cytotoxic and cytostatic activities against various human malignant tumor cells. In a continuation, we evaluated cytotoxic activity of OSW-1 derivatives against HL-60 human leukemia cells and revealed the structure-activity relationships. The cytotoxicity of steroidal saponins were also examined. The results are as follows.1) A total of 24 OSW-1 derivatives, 19 of which were isolated from the bulbs of O. saundersiae, O. thyrsoides, and Galtonia candicans, and 5 of which were chemically synthesized, were evaluated for their cytotoxic activity against HL-60 cells, leading to the new findings of the structure-activity relationships of the OSW-1 related compounds. The role of the acylated diglycoside group attached at C-16 of the aglycon for the appearance of the potent cytotoxicity has not been revealed, and we consider that the assignment of the role … More would finally lead the development of a new anticancer agent with new pharmacological mechanism.2) Two new cholestane glycosides, named galtonioside A (1) and candicanosoide A (2), were isolated from G, candicans and their structures were formulated by spectroscopic and chemical methods. Compounds 1 and 2 showed strong cytotoxic activity against HL-60 cells, which was as potent as the clinically applied anticancer agents, etoposide and methotrexate. In the Jpn. Fdn. for Cancer Res. 38 cell line assay, 1 and 2 displayed differential cytotoxicities, with breast cancer, CNS cancer, and lung cancer subpanel cell lines showing particular sensitivity but with colon cancer, ovarian cancer, and stomach cancer subpanel cell lines being relatively resistant to them. The pattern of differential cytotoxicity of 1 and 2 was evaluated by Compare Program and was revealed not to be correlated with that shown by any of the other compounds including currently used anticancer drugs (correlation coefficient value is about 0.5). This indicates that 1 and 2 may have a unique mode of action and the potentiality as the leads of new anticancer agents.3) The cytotoxic activities of the steroidal saponins mainly isolated from the Liliaceae plants against HL-60 cells were examined. Some steroidal saponins evaluated showed considerable cytotoxic activities, which were almost as potent as that of etoposide used as a positive control. The activities were found to be sensitive to the monosaccharides constituting the sugar moieties and their sequences, as well as to the structures of the aglycons. " Less

以前，我们已经发现，从虎眼万年青鳞茎中分离的酰化胆甾烷糖苷（XDSW-1）对多种人类恶性肿瘤细胞显示出强的细胞毒和细胞抑制活性。在后续工作中，我们评估了OSW-1衍生物对HL-60人白血病细胞的细胞毒活性，并揭示了构效关系。并对甾体皂苷的细胞毒性进行了研究。结果如下：1）共分离得到24个OSW-1衍生物，其中19个是从O. saundersiae，O. thyrsoides，Galtonia candicans，并对其中5个化合物进行了化学合成，评价了它们对HL-60细胞的细胞毒活性，从而对OSW-1相关化合物的构效关系有了新的发现。糖苷配基C-16上的酰化双糖苷基团对出现强效细胞毒性的作用尚未揭示，我们认为该作用的分配 ...更多信息 2）从白念珠菌中分离得到两个新的胆甾烷苷类化合物，分别命名为galtoniosideA（1）和candicanosoideA（2），并通过光谱和化学方法确定了它们的结构。化合物1和2对HL-60细胞具有较强的细胞毒活性，其活性与临床应用的抗癌药物依托泊苷和甲氨蝶呤相当。在日本。Fdn.对于Cancer Res.38细胞系测定，1和2显示出不同的细胞毒性，乳腺癌、CNS癌和肺癌亚组细胞系显示出特别的敏感性，但结肠癌、卵巢癌和胃癌亚组细胞系对它们相对具有抗性。通过比较程序评价了1和2的差异细胞毒性模式，并显示与包括目前使用的抗癌药物在内的任何其他化合物所显示的差异细胞毒性模式不相关（相关系数值约为0.5）。这表明化合物1和2可能具有独特的作用机制，具有作为新型抗癌药物先导化合物的潜力。3）研究了主要从百合科植物中分离得到的甾体皂苷类化合物对HL-60细胞的细胞毒活性。评价的一些甾体皂苷显示出相当大的细胞毒性活性，其几乎与用作阳性对照的依托泊苷一样有效。活性被认为是敏感的单糖构成的糖部分和它们的序列，以及糖基的结构。“减

项目成果

Mimaki Yoshihiro: "Cytotoxic activities and structure-cytotoxic relationships of steroidal saponins"Biol. Pharm. Bull.. 24. 1286-1289 (2001)

Mimaki Yoshihiro：“甾体皂苷的细胞毒性活性和结构-细胞毒性关系”Biol。

Mimaki Yoshihiro: "Flavonol glycosides and steroidal saponins from the leaves of Cestrum nocturnum and their cytotoxicity."J.Nat.Prod. 64(1). 17-22 (2001)

Mimaki Yoshihiro：“来自 Cestrum nocturnum 叶子的黄酮醇糖苷和甾体皂苷及其细胞毒性。”J.Nat.Prod。

Kuroda Minpei: "Cholestane glycosides from the bulbs of Galtonia candicans and their cytotoxicity."Chem.Pham.Bull. 49(8). 1042-1046 (2001)

Kuroda Minpei：“来自 Galtonia candicans 球茎的胆甾烷糖苷及其细胞毒性。”Chem.Pham.Bull。

S. Furuya, F. Takayama, Y. Mimaki, et al.: "Cytotoxic Activity of Saponins from Camassia leichtlinii against Human Oral Tumor Cell Lines"Anticancer Res.. 21・2A. 959-964 (2001)

S.Furuya、F.Takayama、Y.Mimaki 等：“Camassia leichtlinii 皂苷对人口腔肿瘤细胞系的细胞毒性活性”Anticancer Res.. 21・2A (2001)。

Mimaki Yoshihiro: "Candicanoside A, a novel cytotoxic rearranged cholestane glycoside from Galtonia candicans"Helv. Chim. Acta. 83. 2698-2707 (2000)

Mimaki Yoshihiro：“Candicanoside A，一种来自 Galtonia candicans 的新型细胞毒性重排胆甾烷糖苷”Helv。