Le Thanh C, Berlin K Darrell, Benson Stacy D, Eastman Margaret A, Bell-Eunice Gianna, Nelson Anna C, Benbrook Doris M
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
Open Med Chem J. 2007 Oct 24;1:11-23. doi: 10.2174/1874104500701010011.
The Flex-Het compound 10a (SHetA2-NSC 721689) {[4-nitrophenylamino][(2,2,4,4-tetramethylthiochroman-6-yl)amino]methane-1-thione]} has shown promise in preclinical testing as an anti-cancer agent without evidence of toxicity, skin irritancy, or teratogenicity. One objective of this study was to synthesize a series of heteroarotinoids structurally related to SHetA2 and to measure the effect of structural alterations on the cytotoxicity activities of the compounds on A2780 ovarian cancer cells. Alterations included comparisons of activity of an NO2 end group versus a CO2Et end group, a thiourea linker versus a urea linker, and a distorted, thiochroman ring unit versus a planar quinoline ring unit. Cytotoxicity assays demonstrated the thiourea linker compounds to be similar in potency to the urea linker counterparts, the NO2 substitutions were slightly more potent than the CO2Et substitutions, and replacement of the thiochroman group with a planar quinoline fused ring system markedly reduced activity. The mechanism of cytotoxicity through apoptosis was confirmed for the compounds. The optimal combination of structural features for enhancing potency consisted of a urea linker, a NO2 substitution, and a flexible thiochroman unit. Extensive H-bonding in the more active urea derivative was confirmed by X-ray and NMR analyses. This is the first example in which the biological activity of flexible, thiochroman units is compared to that of fused aryl units in a heteroarotinoid molecule.
Flex-Het化合物10a（SHetA2-NSC 721689）{[4-硝基苯氨基][(2,2,4,4-四甲基硫代苯并二氢吡喃-6-基)氨基]甲烷-1-硫酮}在临床前测试中显示出作为抗癌剂的潜力，且无毒性、皮肤刺激性或致畸性证据。本研究的一个目标是合成一系列与SHetA2结构相关的杂芳维甲酸，并测量结构改变对这些化合物对A2780卵巢癌细胞细胞毒性活性的影响。改变包括比较NO2端基与CO2Et端基的活性、硫脲连接基与脲连接基的活性，以及扭曲的硫代苯并二氢吡喃环单元与平面喹啉环单元的活性。细胞毒性试验表明，硫脲连接基化合物的效力与脲连接基对应物相似，NO2取代比CO2Et取代略强，用平面喹啉稠环系统取代硫代苯并二氢吡喃基团会显著降低活性。证实了这些化合物通过凋亡产生细胞毒性的机制。增强效力的结构特征的最佳组合包括脲连接基、NO2取代和柔性硫代苯并二氢吡喃单元。通过X射线和核磁共振分析证实了活性更高的脲衍生物中存在广泛的氢键。这是第一个在杂芳维甲酸分子中将柔性硫代苯并二氢吡喃单元的生物活性与稠合芳基单元的生物活性进行比较的例子。
