Design and Synthesis of New Antitumor Agents Using Marine Natural Product Lamellarin as A Structural Motif
以海洋天然产物板层素为结构基序设计与合成新型抗肿瘤药物
基本信息
- 批准号:18510188
- 负责人:
- 金额:$ 2.61万
- 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:2006
- 资助国家:日本
- 起止时间:2006 至 2007
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
A marine natural product lamellarin D exhibits potent cytotoxicity against a wide range of cancer cell lines. This compound is also effective for multidrug resistant (MDR)cancer cell lines. We have developed two different types of synthetic routes to lamellarine-class natural products. We have also performed structure-activity relationship studies using synthetic analogues and revealed structural requirements for cytotoxicity. Recently, Bailly and co-workers have reported that the major mechanism of action of lamellarin D is the inhibition of topoisomerase I which is known to be the molecular targent of approved camptotecin-type antitumor agents. We performed collaboration with Bailly group to propose topoisomerase I-DNA-lamellarin D ternary complex model. Based upon this model, we designed 1-dearyllammelarin D and 1-substituted 1-dearyllamellarin D as effective lamellarin D analogues. In the present research project, we planned to develop efficient synthetic routes to these analogues … More and evaluate their antitumor activity.Thus, we have achieved the synthesis of 1-dearyllamellarin D in eight steps using regioselective lithiation of N-benzenesulfony1-3-bromopyrrole as a key reaction. Electrophilic substitutions of the O-protected (by isopropyl group)1-dearyllamellarin D proceeded at the 1-position selectively to give a variety of 1-substituted O-protected 1-dearyllamellarin D s. O-protected 1-bromo-1-dearyllamellarin D underwent palladium-catalyzed cross-coupling (Suzuki-Miyaura coupling)with boronic acids in the presence of CsF-Ag_2O to give the other types of 1-substituted O-protected 1-dearyllamellarin D s in good yields. Deprotection of the isopropyl group of these compounds by boron trichloride gave 1-substituted 1-dearyllamellarin D analogues.The bioassay of these new analogues against a wide range of cancer cell lines is under investigation. A preliminary result indicated 1-dearyllamellarin D exhibited potent cytotoxicity against Hela cells in the level similar to lamellarin D. Less
海洋天然产物海带多糖D对多种癌细胞具有很强的细胞毒性。这种化合物对多药耐药(MDR)癌细胞株也有效。我们已经开发了两种不同类型的合成路线,以获得片状天然产品。我们还使用合成类似物进行了构效关系研究,揭示了细胞毒性的结构要求。最近,Bailly和他的同事们报道了海带多糖D的主要作用机制是抑制拓扑异构酶I,而拓扑异构酶I是已知的喜树碱类抗肿瘤药物的分子靶标。我们与Bailly小组合作,提出了拓扑异构酶I-DNA-层粘连蛋白D三元复合体模型。基于这一模型,我们设计了1-脱芳基薄荷糖苷D和1-取代1-脱芳基薄荷糖苷D作为有效的海带多糖D类似物。在目前的研究项目中,我们计划开发这些类似物…的有效合成路线因此,我们以N-苯磺酰基-3-溴吡咯的区域选择性锂化法为关键反应,实现了1-脱芳基薄层糖素D的八步合成。O-保护(异丙基)1-脱芳基海带多糖D的亲电取代选择性地在1-位进行,得到一系列1-取代O-保护的1-脱芳基海带多糖D S。O-保护的1-溴-1-脱芳基海带多糖D在CSF-Ag_2O存在下与钯催化的交叉偶联(Suzuki-Miyaura偶联)得到其他类型的1-取代O-保护的1-脱芳基海带多糖D S。用三氯化硼去保护这些化合物的异丙基,得到1-取代的1-脱芳基薄荷糖苷D类似物。这些新类似物对多种癌细胞的生物活性正在研究中。初步结果表明,1-脱芳基海带菌素D对Hela细胞有较强的细胞毒作用,与海带菌素D相似。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Palladium-catalyzed cross-coupling of N-benzenesulfonyl-3,4-dibromopyrrole and its application to the total syntheses of lamellarins O, P, Q, and R
- DOI:10.1016/j.tet.2007.10.105
- 发表时间:2008-01-07
- 期刊:
- 影响因子:2.1
- 作者:Fukuda, Tsutomu;Sudo, Ei-ichi;Iwao, Masatomo
- 通讯作者:Iwao, Masatomo
新規抗がん剤の創製を指向したラメラリンD類縁体の設計と合成
设计和合成片层蛋白 D 类似物,用于创建新的抗癌药物
- DOI:
- 发表时间:2008
- 期刊:
- 影响因子:0
- 作者:太田 剛;福田 勉;石橋 郁人;岩尾 正倫
- 通讯作者:岩尾 正倫
海洋天然物ラメラリンα20-サルフェートの全合成
海洋天然产物片层素α20-硫酸盐的全合成
- DOI:
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:山口 智裕;福田 勉;石橋 郁人;岩尾 正倫
- 通讯作者:岩尾 正倫
海洋天然物ラメラリンDを基盤とする新規抗腫瘍活性物質の設計および合成
基于海洋天然产物片层蛋白D的新型抗肿瘤活性物质的设计与合成
- DOI:
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者:太田 剛;福田 勉;石橋 郁人;岩尾 正倫
- 通讯作者:岩尾 正倫
The first total synthesis of lamellarin α 20-sulfate, a selective inhibitor of HIV-1 integrase
- DOI:10.1016/j.tetlet.2006.03.121
- 发表时间:2006-05-29
- 期刊:
- 影响因子:1.8
- 作者:Yamaguchi, Tomohiro;Fukuda, Tsutomu;Iwao, Masatomo
- 通讯作者:Iwao, Masatomo
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IWAO Masatomo其他文献
IWAO Masatomo的其他文献
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{{ truncateString('IWAO Masatomo', 18)}}的其他基金
Development of EGFR-Tyrosine Kinase Inhibitors Effective for Non-Small Cell Lung Cancer Resistant to Gefitinib
开发对吉非替尼耐药的非小细胞肺癌有效的 EGFR-酪氨酸激酶抑制剂
- 批准号:
26293028 - 财政年份:2014
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Elucidation and Control of the Molecular Mechanism of Action of the Multifunctional Antitumor Agents Lamellarins
多功能抗肿瘤药物板层素作用分子机制的阐明与调控
- 批准号:
20310135 - 财政年份:2008
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Chemical Synthesis of marine pyrrole alkaloids effective against multidrug-resistant cancers
化学合成有效对抗多重耐药癌症的海洋吡咯生物碱
- 批准号:
14580612 - 财政年份:2002
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of novel antitumor agents having DNA topoisomerase inhibition activity
具有DNA拓扑异构酶抑制活性的新型抗肿瘤药物的研制
- 批准号:
11680591 - 财政年份:1999
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
STUDIES ON THE SYNTHESIS OF ANTITUMOR PYRROLOIMINOQUINONE MARINE ALKALOIDS
抗肿瘤吡咯亚氨基醌海洋生物碱的合成研究
- 批准号:
09680571 - 财政年份:1997
- 资助金额:
$ 2.61万 - 项目类别:
Grant-in-Aid for Scientific Research (C)