Design, Synthesis and Biological Activity of Anti-HIV Compounds Derived from Teleocidins
Teleocidins 抗 HIV 化合物的设计、合成和生物活性
基本信息
- 批准号:07557377
- 负责人:
- 金额:$ 1.73万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:1995
- 资助国家:日本
- 起止时间:1995 至 1997
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Development of chemotherapy against human immunodeficiency virus (HIV) is currently a challenging problem. Though 12-O-tetradecanoylphorbol-13-acetate(TPA) has anti-HIV activity, it is not suitable for use in vivo as it is too toxic. However, prostratin has been reported as an anti-HIV cytoprotective phorbol with protein kinase C (PKC) binding activity and without apparent tumor promotion activity. Teleocidins are well-known TPA-type tumor promoters. The discovery of prostratin prompted us to investigate the anti-HIV activity of teleocidins. We havefound the anti-HIV activity of teleocidin and of designed molecules that reproduce the stereochemistry of teleocidins.Phorbol esters (TPA) and teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. (-) -B … More enzolactam-V8-310 which is a potent anti-HIV compound with the highest selectivity index among the teleocidin-related derivatives examined, reproduces the active conformation and the other biological activities of teleocidins. We have performed the synthesis of benzolactams with hydrophobic substituents at various positions. Structure-activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also simulated the docking of these teleocidin-type benzolactam molecules to the cys2 domain structure observed in the crystalline complex of PKCd with phorbol 13-acetate. Teleocidins and benzolactams fitted well into the same cavity as phorbol-13-acetate. 0f the three functional groups hydrogen-honding to the protein, two hydrogen-bonded with protein atoms in cmmon with phorbol 13-acetate, but the third one hydrogen-bonded with a different protein atom from that in the case of phorbol-13-acetale. The model explains well the remarkable difference in activity between (-) -BL-V8-310 and its analog having a bulky substituent at C-8. Less
针对人类免疫缺陷病毒(HIV)的化疗的开发目前是一个具有挑战性的问题。 12-O-十四烷酰佛波醇-13-乙酸酯(TPA)虽然具有抗HIV活性,但由于毒性太大,不适合在体内使用。然而,据报道,Prostratin 是一种抗 HIV 细胞保护佛波醇,具有蛋白激酶 C (PKC) 结合活性,但没有明显的肿瘤促进活性。 Teleocidins 是众所周知的 TPA 型肿瘤促进剂。 Prostratin 的发现促使我们研究 teleocidins 的抗 HIV 活性。我们发现了 teleocidin 和可重现 teleocidin 立体化学的设计分子的抗 HIV 活性。已知佛波酯 (TPA) 和 teleocidin 是有效的肿瘤促进剂,并通过与酶竞争性结合来激活蛋白激酶 C (PKC)。由于显着的结构差异,这些化合物的化学结构和活性之间的关系引起了人们的广泛关注。 (-) -B … 更多 enzolactam-V8-310 是一种有效的抗 HIV 化合物,在所检测的 teleocidin 相关衍生物中具有最高的选择性指数,再现了 teleocidin 的活性构象和其他生物活性。我们已经合成了在不同位置具有疏水取代基的苯并内酰胺。结构-活性数据表明,C-2 和 C-9 之间疏水区域的存在以及 C-8 处的空间因子在生物活性的出现中发挥着关键作用。我们还模拟了这些 teleocidin 型苯并内酰胺分子与在 PKCd 与佛波醇 13-乙酸酯的晶体复合物中观察到的 cys2 结构域结构的对接。 Teleocidins 和苯并内酰胺与佛波醇 13-乙酸酯能够很好地装入同一空腔中。 0f 三个官能团与蛋白质形成氢键,其中两个官能团与佛波醇 13-乙酸酯常见的蛋白质原子形成氢键,但第三个官能团与佛波醇 13-乙酸酯的情况不同的蛋白质原子形成氢键。该模型很好地解释了 (-) -BL-V8-310 与其在 C-8 处具有大取代基的类似物之间活性的显着差异。较少的
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Yasuyuki Endo: "Role of the Hydrophobic Moiety of Tumor Promoters.Systhesis and Activity of Benzolactams with Alkyl Substiuents at Various Positions." Chem.Pharm.Bull.45. 424-426 (1997)
Yasuyuki Endo:“肿瘤促进剂的疏水部分的作用。在不同位置具有烷基取代基的苯佐内酰胺的合成和活性。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Azuma, A,, Hashimoto, Y., Yamaguchi, M., Takehana, S., Ando, Y., lwasaki, S., Fukasawa, H., Endo, Y., Shudo, K.: "Photoaffinity Labeling and Affinity Sorbent Gels of Tumor promoter-Binding Protein (CN-TPBP)." Biol.Pharm.Bull. 20. 5-8 (1997)
Azuma, A,、Hashimoto, Y.、Yamaguchi, M.、Takehana, S.、Ando, Y.、lwasaki, S.、Fukasawa, H.、Endo, Y.、Shudo, K.:“光亲和标记和亲和力
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Yasuyuki Endo: "A Novel Conformational Constrained Analogues of Diacyglyceol.Protein Kinase C Affinity of Simplified Compounds Based on 6-Membered Lactam Moiety." BioMed.Chem.Lett.7. 2997-3000 (1997)
Yasuyuki Endo:“一种新型构象受限的二酰基甘油类似物。基于 6 元内酰胺部分的简化化合物的蛋白激酶 C 亲和力。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Yasuyuki Endo: "A Clarification of the Binding Mode of Teleocidin and Benzolacttams to the Cys2 Domain of Protein Kinase Cδ by Synthesis of Hydrophobically Modified.Teleocidin-mimicking Benzolactams and Computational Docking Simulation." J.Med.Chem.41(印刷中
Yasuyuki Endo:“通过合成疏水性修饰的类似 Teleocidin 的苯并内酰胺和计算对接模拟,阐明了 Teleocidin 和苯并内酰胺与蛋白激酶 Cδ 的 Cys2 结构域的结合模式(正在出版)。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Endo, Y., Ohno, M., Takehana, S., Driedger, P.E., Stabel, S., Shudo, K.: "Role of the Hydrophobic Moiety of Tumor Promoters. Synthesis and Activity of Benzolactams with Alkyl Substituents at Various Positions." Chem.Pharm.Bull.45. 424-426 (1997)
Endo, Y.、Ohno, M.、Takehana, S.、Driedger, P.E.、Stabel, S.、Shudo, K.:“肿瘤促进剂疏水部分的作用。在不同位置具有烷基取代基的苯内酰胺的合成和活性
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ENDO Yasuyuki其他文献
ENDO Yasuyuki的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ENDO Yasuyuki', 18)}}的其他基金
A New Development of Molecular Design Utilizing Novel Hydrophobic Structures
利用新型疏水结构的分子设计新进展
- 批准号:
26460151 - 财政年份:2014
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Epidemiological survey for canine tick-borne diseases in Japan
日本犬蜱传疾病流行病学调查
- 批准号:
23580442 - 财政年份:2011
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Development of Receptor Regulators Utilizing Novel HydrophobicStructure and Its Application for Medicinal Drug Design
利用新型疏水结构开发受体调节剂及其在药物设计中的应用
- 批准号:
20390035 - 财政年份:2008
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development and Application of Novel 3-Dimensional Hydrophobic Structures for Drug Design, Which Are Focused on Molecular Recognition between Ligand and Receptor
药物设计中新型三维疏水结构的开发和应用,重点关注配体和受体之间的分子识别
- 批准号:
16390032 - 财政年份:2004
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Study on Electronic and Steric Effects of Boron Cluster and Application for Construction of Functional Molecules.
硼团簇的电子和空间效应研究及其在功能分子构建中的应用。
- 批准号:
13470468 - 财政年份:2001
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Design and Synthesis of Cellular Signal Transduction Modulator, Benzolactam Derivatives and Related Compounds
细胞信号转导调节剂、苯并内酰胺衍生物及相关化合物的设计与合成
- 批准号:
10470463 - 财政年份:1998
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for Scientific Research (B).
Search for New Tumor Promoters Employing Chemical Calculation
利用化学计算寻找新的肿瘤促进剂
- 批准号:
04671288 - 财政年份:1992
- 资助金额:
$ 1.73万 - 项目类别:
Grant-in-Aid for General Scientific Research (C)