Liu Xiaoling, Go Mei-Lin
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Bioorg Med Chem. 2007 Nov 15;15(22):7021-34. doi: 10.1016/j.bmc.2007.07.042. Epub 2007 Aug 21.
A library of chalcones with different basic groups were synthesized and evaluated for antiproliferative activities against the human breast cancer (MCF 7) and colon cancer (HCT 116) cell lines. Structure-activity relationships were analyzed by projection methods (PCA/PLS) and multiple linear regression. Polar volume, hydrogen bonding features, HOMO energies, and charge on the beta carbon were found to be important factors. A basic group on either ring A or B of the chalcone led to a favourable increase in polar volume, but when present on ring B, it increased HOMO energies and decreased the positive charge on the beta carbon, both of which led to lower activity. Several examples showed that final activity of the chalcone was influenced by compensatory interactions among these parameters. In general, a single basic group on ring A was associated with good activity. A notable exception was compound 1-123 which had basic groups on both rings A and B but still maintained a good activity profile with IC(50)<10 microM and selectivity ratios >2.5. There was some evidence to show that structural differences in chalcones influenced not only activity but mechanism of action. Compounds 6-130 and 7-140 which had basic groups on ring A interfered with cell cycle progression, but the dibasic chalcone 1-123 had no effect.
合成了一系列带有不同碱性基团的查尔酮，并对其针对人乳腺癌（MCF 7）和结肠癌（HCT 116）细胞系的抗增殖活性进行了评估。通过投影方法（PCA/PLS）和多元线性回归分析了构效关系。发现极性体积、氢键特征、HOMO能量以及β碳上的电荷是重要因素。查尔酮A环或B环上的碱性基团会使极性体积有利地增加，但当存在于B环上时，会增加HOMO能量并降低β碳上的正电荷，这两者都会导致活性降低。几个例子表明，查尔酮的最终活性受这些参数之间的补偿相互作用影响。一般来说，A环上的单个碱性基团与良好活性相关。一个显著的例外是化合物1-123，其A环和B环上都有碱性基团，但仍保持良好的活性谱，IC(50)<10 microM且选择性比率>2.5。有一些证据表明，查尔酮的结构差异不仅影响活性，还影响作用机制。A环上有碱性基团的化合物6-130和7-140会干扰细胞周期进程，但二元查尔酮1-123没有影响。
