Photoactivatable Enediyne Antibiotics

光活化烯二炔抗生素

• 批准号: 6456605
• 负责人: VLADIMIR V POPIK
• 金额: $ 13.62万
• 依托单位: BOWLING GREEN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2005-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456605
• 关键词: DNA binding protein; antineoplastic antibiotics; azo compounds; carbonyl compound; chemical cleavage; cyclization; drug design /synthesis /production; enzyme activity; ketones; nuclease; photoactivation; ruthenium

DESCRIPTION: (provided by applicant) A pilot study designed to test the feasibility of photoactivatable analogs of natural enediyne antitumor antibiotics is proposed. We will modify the enediyne core of the molecule responsible for the cytotoxicity of these natural products, making it inactive in the dark but readily activatable by light. To achieve this goal we plan to explore a novel mode of photoactivation, the in situ generation of active enediyne fragment. This will be done by employing two strategies: 1) the photochemical ring contraction of eleven-membered ring enediynes and 2) the in situ photochemical formation of pi-component of the enediyne conjugated system. Four photochemical reactions known to provide a high quantum yield of the products will be examined as enediyne activators: 1) photo-Wolff reaction of alpha-diazodicarbonyl compounds; 2) decarbonylation of cyclopropenones; 3) Norrish type II cleavage of alpha-diketones; and 4) photochemical ligand exchange in ruthenium complexes. We plan to explore the suitability of the above reactions for enediyne activation and the stability of corresponding precursors. We will then synthesize cyclic enediynes incorporating selected photoreactive moieties and investigate their photoactivation and DNA cleavage abilities. The most active systems will be conjugated with a DNA-binding molecule for the in vitro testing of photonuclease efficiency. The results of this investigation are expected to serve as a basis for the development of new photoactivatable enediyne anticancer agents. These compounds should be non-toxic in the dark but be selectively activated in the target tissue by light of an appropriate wavelength. Since the simultaneous presence of both photoactivatable antibiotics and light are required to develop cytotoxicity, damage to healthy tissues can be minimized.

描述：（由申请人提供）一项旨在测试的试点研究 天然Enediyne抗肿瘤的光活化类似物的可行性 提出了抗生素。我们将修改分子的Enediyne核心 负责这些天然产品的细胞毒性，使其不活跃 在黑暗但很容易被光激活。为了实现这一目标，我们计划 探索一种新型的光活化模式 Enediyne碎片。这将通过采用两种策略来完成：1） 11元环的光化环收缩和2） Enediyne共轭系统的PI组分的原位光化学形成。 已知的四种光化学反应可提供高量子产率 产品将被检查为Enediyne激活剂：1） α-Diasodicarbonyl化合物； 2）环丙酮的脱轴偶像化； 3） Norrish II型α-二酮的裂解； 4）光化学配体 在钌配合物中进行交换。我们计划探讨 上述反应，以进行endiyne激活和相应的稳定性 前体。然后，我们将合成循环endiynes，以结合所选的 光反应性部分并研究其光活化和DNA裂解 能力。最活跃的系统将与DNA结合结合 用于体外测试光核酸酶效率的分子。 预计这项调查的结果将作为 开发新的光活化Enediyne抗癌剂。这些化合物 在黑暗中应无毒，但在目标中有选择性激活 通过适当的波长进行组织。自同时存在 需要光活化的抗生素和光 细胞毒性，对健康组织的损害可以最小化。