Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA.
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1217A, Oklahoma City, OK 73104, USA.
Eur J Med Chem. 2015;96:209-17. doi: 10.1016/j.ejmech.2015.03.070. Epub 2015 Apr 4.
Flexible Heteroarotinoids (Flex-Hets) are a class of substituted di-aryl compounds that exhibit potent anti-cancer activity without toxicity. They were derived from the more conformationally restricted, 2-atom linker Hets by substitution of the 2-atom linker with a 3-atom urea or thiourea linker, which conferred more potent inhibitory activity against cancer cell lines. The objectives of this structure activity relationship (SAR) study were to determine if a 4-atom acrylamide linker and various substitutions on the terminal aryl ring altered the anti-cancer activity of these second generation Flex-Het compounds compared to the parent Flex-Het compound, SHetA2, which has a thiourea linker and a nitro substituent. Biological activity was measured using a cytotoxicity assay of the human A2780 ovarian cancer cell line treated with a range of compound concentrations. Nitrogen-based substitutions on the terminal aryl group caused similar, but slightly reduced efficacies and potencies. Exceptions were systems that had a nitro group at the para position, the potencies of which were better than that of SHetA2 with efficacies that were only slightly reduced compared to SHetA2. Similarly, the potency of the system with a para dimethylamino group was greater than that of SHetA2. However, a 30% reduction in efficacy compared to SHetA2 was noted. While specific members with the 4-atom acrylamide linker did exhibit excellent potency, the efficacy was slightly below that of SHetA2. Thus, a gradient of activities was observed as the substituent on the aryl ring was altered.
柔性杂芳环化合物（Flex-Hets）是一类取代的二芳基化合物，具有强大的抗癌活性而无毒性。它们是由更具构象限制的 2 原子连接体 Het 衍生而来，通过用 3 原子脲或硫脲连接体取代 2 原子连接体，从而赋予了对癌细胞系更强的抑制活性。这项构效关系（SAR）研究的目的是确定 4 原子丙烯酰胺连接体和末端芳环上的各种取代基是否会改变这些第二代 Flex-Het 化合物的抗癌活性，与具有硫脲连接体和硝基取代基的母体 Flex-Het 化合物 SHetA2 相比。使用人 A2780 卵巢癌细胞系的细胞毒性测定来测量生物活性，该细胞系用一系列化合物浓度处理。末端芳基上的含氮取代基引起相似但略有降低的功效和效力。例外的是在对位具有硝基取代基的系统，其效力优于 SHetA2，而功效仅略低于 SHetA2。同样，具有对位二甲氨基取代基的系统的效力大于 SHetA2。然而，与 SHetA2 相比，功效降低了 30%。虽然具有 4 原子丙烯酰胺连接体的特定成员确实表现出优异的效力，但功效略低于 SHetA2。因此，随着芳环上取代基的改变，观察到活性的梯度。
