通过C(sp3) -C(sp3) 的照片解恢复β-拉帕的活性
Esther G Kaye1,2, Bijan Mirabi3, Ivonne R Lopez-Miranda1,2
1Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
Journal of the American Chemical Society
|June 2, 2023
概括
研究人员开发了一种针对β-lapachone的新型摄影策略, 这种前期药物方法使用独特的C-C键裂变被光激活,降低毒性并使癌症治疗中可控的药物释放.
科学领域:
- 医学化学
- 有机化学
- 摄影化学
背景情况:
- 拉帕是一种具有抗增殖功能的天然产品,但具有全身毒性.
- 可移动的保护组提供一种控制药物释放和最小化毒性的策略.
- 现有的光主要针对核友位,限制了像β-lapachone这样的电友化合物的应用.
研究的目的:
- 开发一种使用C(sp3) -C(sp3) 与氨酸光结合的β-lapachone新型光结合策略.
- 为了证明从前药物中诱导活性β-lapachone的释放.
- 研究C-C键裂解的机制,并探索其适用于α-lapachone.
主要方法:
- 通过C ((sp3) -C ((sp3)) 键,对β-拉帕的电友性子部分进行共价无活化.
- 在人体全血中评估前药物稳定性和在黑暗中的毒性.
- 在可见光激活时对NQO1酶和人类癌细胞的药物释放和生物活性的评估.
- 对光诱导的C-C键裂变的机制研究.
主要成果:
- 设计的β- 拉帕前药在人体全血中保持完整,没有表现出暗毒性.
- 光激活成功地分裂了C-C键,释放了活性β-拉帕并恢复了抗增殖活性.
- 一个非传统的,基于激素的机制涉及电荷转移激发状态被提出为C-C键裂变.
- 对异构α- 拉帕成功应用了光化策略.
结论:
- 已经开发出一种新型的光化策略,用于像β-拉帕和α-拉帕这样的电友.
- 这种方法利用独特的光诱导的C-C键裂变,为药物释放提供时空控制.
- 该策略将毒性降低至最低,并扩大光化合物的化学工具箱,并为其他子提供潜在的应用.
相关概念视频
00:57C–C Bond Cleavage: Retro-Aldol Reaction
5.9K
The reverse of the aldol addition reaction is called the retro-aldol reaction. Here, the carbon–carbon bond in the aldol product is cleaved under acidic or basic conditions to form two molecules of carbonyl compounds. The mechanism of the reaction consists of three steps.
In the first step, as depicted in Figure 1, the base deprotonates the β-hydroxy ketone at the hydroxyl group to form an alkoxide ion.
In the first step, as depicted in Figure 1, the base deprotonates the β-hydroxy ketone at the hydroxyl group to form an alkoxide ion.
5.9K
01:12Cycloaddition Reactions: MO Requirements for Photochemical Activation
2.1K
Some cycloaddition reactions are activated by heat, while others are initiated by light. For example, a [2 + 2] cycloaddition between two ethylene molecules occurs only in the presence of light. It is photochemically allowed but thermally forbidden.
2.1K
01:26Photochemical Electrocyclic Reactions: Stereochemistry
1.9K
The absorption of UV–visible light by conjugated systems causes the promotion of an electron from the ground state to the excited state. Consequently, photochemical electrocyclic reactions proceed via the excited-state HOMO rather than the ground-state HOMO. Since the ground- and excited-state HOMOs have different symmetries, the stereochemical outcome of electrocyclic reactions depends on the mode of activation; i.e., thermal or photochemical.
Selection Rules: Photochemical Activation
Selection Rules: Photochemical Activation
1.9K
01:02Long-patch Base Excision Repair
7.1K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.1K
01:26Thermal and Photochemical Electrocyclic Reactions: Overview
2.4K
Electrocyclic reactions are reversible reactions. They involve an intramolecular cyclization or ring-opening of a conjugated polyene. Shown below are two examples of electrocyclic reactions. In the first reaction, the formation of the cyclic product is favored. In contrast, in the second reaction, ring-opening is favored due to the high ring strain associated with cyclobutene formation.
2.4K
![[3,3] Sigmatropic Rearrangement of 1,5-Dienes: Cope Rearrangement](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2Ffiles%2Fmedia%2Fscience-education%2Fscience-education-thumbs%2F12422.jpg&w=3840&q=75)
01:21[3,3] Sigmatropic Rearrangement of 1,5-Dienes: Cope Rearrangement
2.8K
The Cope rearrangement is classified as a [3,3] sigmatropic shift in 1,5-dienes, leading to a more stable, isomeric 1,5-diene. The reaction involves a concerted movement of six electrons, four from two π bonds and two from a σ bond, via an energetically favorable chair-like transition state.
2.8K