AN Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova str 28, 119991 Moscow, Russia.
Eur J Med Chem. 2010 Mar;45(3):992-1000. doi: 10.1016/j.ejmech.2009.11.041. Epub 2009 Nov 26.
In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-omega-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by (1)H, (31)P, (13)C NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl(3) solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5-bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated.
为了设计具有改进的 3,5-双（噻吩亚基）哌啶-4-酮型抗肿瘤活性的试剂，通过母体 NH-3,5-双（噻吩亚基）哌啶-4-酮的直接磷酸化和预形成的 N-膦基取代的哌啶酮与噻吩-2-甲醛的缩合，分别得到 E,E-N-膦酰基-3,5-双（噻吩亚基）哌啶-4-ones 6a-c 和 E,E-N-ω-膦酰基烷基-3,5-双（噻吩亚基）哌啶-4-ones 7a-c。通过（1）H、（31）P、（13）C NMR 以及单晶 X 射线衍射分析确定了化合物的结构。在可见光的作用下，热力学上更稳定的 E,E-异构体在 CDCl3 溶液中缓慢经历光化学转化为相应的 E,Z-异构体，并且以单独的状态分离出 E,Z-N-甲基-3,5-双（噻吩亚基）哌啶-4-one 5。证明了 3,5-双（噻吩亚基）哌啶-4-酮的磷酸化对人癌细胞系 Caov3、Scov3 和 A549 的细胞毒性性质的重要性，以及烯烃构型对抗肿瘤活性的影响。
