Molecular Function of Naturally Occurring Anti-microtubule Agent Phenylahistin (Determination of Structural Components Necessary for the Anti-microtubule activity t and Molecular Design for Drugs)
天然存在的抗微管剂苯拉西汀的分子功能(抗微管活性所需结构成分的测定和药物分子设计)
基本信息
- 批准号:12672162
- 负责人:
- 金额:$ 1.98万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2000
- 资助国家:日本
- 起止时间:2000 至 2002
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Taxanes and the vinca alkaloids are routinely used as the anti-microtubule agents in the clinic, however after long-term treatment, tumors typically become resistant to these compounds. Hence, there is a significant interest in the development of novel anti-microtubule agents for use in clinical oncology. As one of such candidates, we are focusing on a fungal product, phenylahistin (PLH), which belongs to a new class of peptidic colchicine-like microtubule-binding agents that exhibits cytotoxic activity against a wide variety of tumor cell lines. (-)-Phenylahistin (-)-1, a diketopiperazine derivative, consists of L-phenylalanine and a unique isoprenylated dehydrohistidine residue with a quaternary carbon at the 5-position of the imidazole ring. To develop more potent anti-tumor agents based on this diketopiperazine derivative, we investigated to elucidate the structural components necessary for the anti-microtubule activity of (-)-1, then performed the total synthesis of 1 for establish the synthetic route of its derivatives as well. From the biological evaluation of synthetic PLH derivatives, we found that a rigid and planar pseudo-tricyclic structure and the existence of the gem-dimethyl structure at the 5-position of the imidazole ring are important factors to elicit the potent cytotoxic activity. By utilizing this established synthetic route, we synthesized several derivatives of (-)-1, whose substituent at the 5-position of the imidazole ring was modified with different alkyl chains, to determine the effect of this moiety on the biological activity. From the evaluation of derivatives, it is suggested that the existence of the gem-dimethyl structure at this position is important to elicit higher cytotoxic activity.Further derivatization of (-)-1 using the developed synthetic method will contribute to a better understanding on the structure-activity relationship of phenylahistin and to develop more potent antitumor agents based on the diketopiperazine structure.
紫杉烷和长春花生物碱在临床上通常用作抗微管剂,然而在长期治疗后,肿瘤通常对这些化合物产生耐药性。因此,在开发用于临床肿瘤学的新型抗微管剂方面存在显著的兴趣。作为这样的候选人之一,我们专注于真菌产品,phenylahistin(PLH),它属于一类新的肽类秋水仙素样微管结合剂,对各种各样的肿瘤细胞系表现出细胞毒活性。(-)-苯基组氨酸(-)-1是一种二酮哌嗪衍生物,由L-苯丙氨酸和独特的异戊二烯化脱氢组氨酸残基组成,在咪唑环的5-位具有季碳。为了开发更有效的抗肿瘤药物,我们首先研究了(-)-1抗微管活性所必需的结构组分,然后进行了1的全合成,建立了其衍生物的合成路线。从合成的PLH衍生物的生物学评价,我们发现,一个刚性和平面的伪三环结构和存在的偕二甲基结构在5-位的咪唑环是重要的因素,以引起有效的细胞毒活性。利用这一合成路线,我们合成了几种咪唑环5位取代基被不同的烷基链修饰的(-)-1衍生物,以确定该部分对生物活性的影响。对衍生物的评价表明,(-)-1的偕二甲基结构的存在对提高其细胞毒活性具有重要意义,进一步的衍生化将有助于更好地理解苯拉希汀的构效关系,并有助于开发基于二酮哌嗪结构的抗肿瘤药物。
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kaneo Kanoh et al.: "Synthesis and Biological Activities of Phenylahistin Derivatives"Peptide Science. 1999. 409-412 (2000)
Kaneo Kanoh 等:“苯拉希汀衍生物的合成和生物活性”肽科学。
- DOI:
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- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Y.Hayashi, S.Orikasa, K.Tanaka, K.Kanoh, Y.Kiso: "Total Synthesis of Anti-microtubule Diketopiperazine Derivatives : Phenylahistin and Aurantiamine"Journal of Organic Chemistry. 65. 8402-8405 (2000)
Y.Hayashi、S.Orikasa、K.Tanaka、K.Kanoh、Y.Kiso:“抗微管二酮哌嗪衍生物的全合成:苯拉司汀和橙胺”有机化学杂志。
- DOI:
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- 影响因子:0
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- 通讯作者:
E.Ami, Y.Hayashi, Y.Kiso, 他4名: "Synthesis of novel amino acid, L-bis-tetrahydrofuranylglycines"Tetrahedron Letters. 43・16. 2931-2934 (2002)
E.Ami、Y.Hayashi、Y.Kiso 等 4 人:“新型氨基酸 L-双四氢呋喃甘氨酸的合成”Tetrahedron Letters 43・16 (2002)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
K.Kanoh Y.Hayashi,J.Katada,S.Kohno,I.Uno,Y.Kiso: "Synthesis and Biological Activitities of Phenylahistin Derivatives."Peptide Science. 1999. 409-412 (2000)
K.Kanoh Y.Hayashi、J.Katada、S.Kohno、I.Uno、Y.Kiso:“苯拉希汀衍生物的合成和生物活性。”肽科学。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
K.Kanoh, S.Kohno, J.Katada, J.Takahashi, I.Uno, Y.Hayashi: "Synthesis and Biological Activities of Phenylahistin Derivatives"Bioorganic Medicinal Chemistry. 7. 1451-1457 (1999)
K.Kanoh、S.Kohno、J.Katada、J.Takahashi、I.Uno、Y.Hayashi:“苯拉希汀衍生物的合成和生物活性”生物有机药物化学。
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HAYASHI Yoshio其他文献
HAYASHI Yoshio的其他文献
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{{ truncateString('HAYASHI Yoshio', 18)}}的其他基金
Study on Medicinal Chemistry of Reversible Cysteine Protease Inhibitors for the Treatment of Infectious Diseases
可逆性半胱氨酸蛋白酶抑制剂治疗感染性疾病的药物化学研究
- 批准号:
23659059 - 财政年份:2011
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Integrated medicinal chemistry research of intractable diseases based on peptidic small molecules
基于肽类小分子的疑难杂症综合药物化学研究
- 批准号:
23390029 - 财政年份:2011
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Immunotherapeutic analysis using newly established murine models for Sjogren' s syndrome
使用新建立的干燥综合征小鼠模型进行免疫治疗分析
- 批准号:
21249090 - 财政年份:2009
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents
基于微管靶向药物的抗癌药物化学、化学生物学和化学药剂学研究
- 批准号:
20390036 - 财政年份:2008
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular analysis of pathogenesis on Sjogren's syndrome and its application of new diagnosis and therapy
干燥综合征发病机制的分子分析及其在新诊治中的应用
- 批准号:
17109016 - 财政年份:2005
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (S)
Development of Anticancer and Antiviral Agents Based on Diketopiperazine as a Bio-function-Mimicking Molecular Platform
基于二酮哌嗪作为生物功能模拟分子平台的抗癌和抗病毒药物的开发
- 批准号:
15590102 - 财政年份:2003
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development research into history chronology system that can share collaborative activity and data by network
可通过网络共享协作活动和数据的历史年代学系统的开发研究
- 批准号:
15500152 - 财政年份:2003
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Chemical composition and point source of high energy primary cosmic ray and sidereal time variation
高能初级宇宙线的化学成分、点源和恒星时变
- 批准号:
15403005 - 财政年份:2003
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of disease-specific diagnosis and immunotherapy for Sjogren's syndrome
干燥综合征的疾病特异性诊断和免疫治疗的发展
- 批准号:
12557022 - 财政年份:2000
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Analysis of the mechanism of membranous proteolysis and the immunoregulation for Sjogren's syndrome
干燥综合征膜蛋白水解机制及免疫调节分析
- 批准号:
12307040 - 财政年份:2000
- 资助金额:
$ 1.98万 - 项目类别:
Grant-in-Aid for Scientific Research (A)