整形替代能否增强3,5-bis () -4-piperidones系列中的细胞毒性作用?
Subhas S Karki1,2, Umashankar Das1, Jan Balzarini3
1College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
Medicines (Basel, Switzerland)
|November 25, 2024
概括
新的细胞毒性化合物 (3,5-基-4-piperidones) 与整形替代剂显示出对癌细胞的增强效力. 这项研究探讨了潜在的抗癌药物开发的结构-活性关系.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 癌症研究 癌症研究
背景情况:
- 一系列的3,5-基-4-piperidones (化合物1a-n) 的合成.
- 这项研究的目的是测试与类似物相比,正位置换的环是否会增强细胞毒性效力.
研究的目的:
- 为了评估合成的3,5-二烯-4-piperidones对各种癌症细胞系的细胞毒性活动.
- 调查结构特征 (间平面角度,脂性) 与细胞毒性功效之间的相关性.
- 评估针对瘤与非恶性细胞的瘤选择性毒性.
主要方法:
- 对人类 (Molt/4C8,CEM) 和小鼠 (L1210) 癌细胞系进行1a-n化合物的生物评估.
- 对平面间角 (θA, θB) 和细胞毒性强度 (IC50值) 的相关性分析.
- 使用Hansch pi (π) 值进行定量结构-活动关系 (QSAR) 分析.
- 对特定癌细胞系 (HSC-2,HSC-3,HSC-4,HL60) 和非恶性细胞 (HGF,HPC,HPLF) 的评估.
主要成果:
- 在Molt4/C8细胞中观察到平面间角 θA和IC50值之间存在正相关性.
- 在QSAR分析中,亚里尔替代剂汉斯奇pi (π) 值与IC50与Molt4/C8和CEM细胞之间存在正相关性.
- 1系列中的迪昂与非恶性细胞相比,对被测试的新生体具有更高的瘤选择性毒性.
结论:
- 生物评价结果部分支持了 орто替代剂增强细胞毒性功效的假设.
- 结构修改,特别是骨架替代,可以影响3,5-基-4-piperidones的抗癌活性.
相关概念视频
Directing Effect of Substituents: ortho–para-Directing Groups
6.2K
Ortho–para directors are substituent groups attached to the benzene ring and direct the addition of an electrophile to the positions ortho or para to the substituent. All electron-donating groups are considered ortho–para directors. They donate electrons to the ring and make the ring more electron-rich. The ring is therefore susceptible to the addition of electrophiles. Substituents such as amino, hydroxy, or alkoxy, containing lone pairs on the atom adjacent to the ring, donate...
6.2K
ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3
5.8K
All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
5.8K
Directing and Steric Effects in Disubstituted Benzene Derivatives
2.9K
When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the...
2.9K
Directing Effect of Substituents: meta-Directing Groups
4.4K
Substituents on the benzene ring that direct an incoming electrophile to undergo substitution at the meta position are called meta directors. All meta directors either have a positive charge on the atom directly bonded to the ring or a partial positive charge. These groups function by withdrawing electrons from the ring through inductive and resonance effects. Consider the carbocation intermediates formed upon the addition of an electrophile on nitrobenzene at the...
4.4K
ortho–para-Directing Deactivators: Halogens
5.4K
Halogens are ortho–para directors. They are more electronegative than carbon. Therefore, as ring substituents, they can withdraw electrons through the inductive effect and deactivate the aromatic ring towards electrophilic substitution. Halogens also have an electron-donating resonance effect on the ring, which influences the orientation of the incoming electrophile. If an electrophile attacks at the ortho or the para position, the halogen donates electrons and stabilizes the intermediate...
5.4K
meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H
5.4K
All meta-directing substituents are deactivating groups. These substituents withdraw electrons from the aromatic ring, making the ring less reactive toward electrophilic substitution. For example, the nitration of nitrobenzene is 100,000 times slower than that of benzene because of the deactivating effect of the nitro group. The first step in an electrophilic aromatic substitution is the addition of an electrophile to form a resonance-stabilized carbocation. The energy diagrams for...
5.4K


