Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography
Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography
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DOI：
10.1021/jm010559p
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发表时间：
2002-07-04
影响因子：
7.3
通讯作者：
Stables, JP
中科院分区：
文献类型：
--
作者：
Dimmock, JR;Zello, GA;Stables, JP
制备了三个系列的2-亚芳基苯并环烷酮1-3，以比较分子的形貌和细胞毒性。这些化合物含有两个芳环，其空间关系受到脂环的大小和亚芳基芳环中取代基的性质的影响。针对鼠P388和L1210细胞以及人Molt 4/C8和CEM T淋巴细胞评价所有化合物。从这些结果中，11和2c，1显示为有用的先导分子，并且11显示出显著抑制L1210细胞中的大分子DNA、RNA和蛋白质合成。通过X射线晶体学测定了19种代表性化合物的各种原子间距离、键角和扭转角，并在近40%的检查病例中注意到这些数据与细胞毒性之间的相关性。结构-活性关系表明，在一般情况下，在亚芳基芳环中的基团的空间位阻性质，所揭示的摩尔吸光活性值的测量，比芳基取代基的电子和疏水性质的生物活性的贡献。这些化合物显示出很小的鼠毒性，这有利于决定开发这些分子作为细胞毒性和抗癌剂。
Three series of 2-arylidenebenzocycloalkanones 1-3 were prepared in order to compare the topography of the molecules with cytotoxicity. These compounds contain two aryl rings whose spatial relationships to each other were influenced by the size of the alicyclic ring and the nature of the substituents in the arylidene aryl rings. All compounds were evaluated against murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. From these results, 1l and 2c,l emerged as useful lead molecules and 1l was shown to significantly inhibit macromolecular DNA, RNA, and protein syntheses in L1210 cells. Various interatomic distances, bond angles, and a torsion angle of 19 representative compounds were determined by X-ray crystallography, and correlations between these data and the cytotoxicity were noted in nearly 40% of the cases examined. Structure-activity relationships revealed that in general, the steric properties of the groups in the arylidene aryl ring, as revealed by measurements of the molar refractivity values, contributed more to bioactivity than the electronic and hydrophobic properties of the aryl substituents. The compounds displayed little murine toxicity, which favors the decision to develop these molecules as cytotoxic and anticancer agents.