Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, United States.
Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
Bioorg Med Chem. 2020 Jan 1;28(1):115244. doi: 10.1016/j.bmc.2019.115244. Epub 2019 Dec 2.
SHetA2 (NSC 721689), our lead Flex-Het anti-cancer agent, consists of a thiochroman (Ring A) and a 4-nitrophenyl (Ring B) linked by a thiourea bridge. In this work, several series of new analogs having a tetrahydroquinoline (THQ, Ring A) unit connected by a urea or thiourea linker to a 4-substituted phenyl (Ring B) have been prepared and evaluated relative to SHetA2 in terms of binding affinity with mortalin and inhibition of A2780 ovarian cancer cells. Six of the derivatives equaled or exceeded the efficacy shown by SHetA2. Compounds 1a-d (series 1), lacking a methyl on the Ring A nitrogen and the gem-dimethyls on the adjacent carbon, showed only weak activity. Salt 2, the quaternized N,N-dimethyl iodide salt analog of 1a, also possessed very modest growth inhibition in the cell line studied. Series 3 compounds, which had a C3 ketone and an N-methyl replacing the sulfur in Ring A, were most successful. Compound 3a [Ring A = 1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl; urea linker; Ring B = 4-nitrophenyl] had slightly lower potency (IC 3.8 μM), but better efficacy (94.8%) than SHetA2 (IC 3.17 μM, efficacy 84.3%). In addition, 3c and 3d [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethyl)phenyl] and 3e and 3f [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethoxy)phenyl] were also evaluated since these agents possessed electron-withdrawing groups with H-bonding capability. All displayed good activity. Compounds 3c and 3e showed improvement in both potency and efficacy compared to SHetA2. In general, when the linker group between Rings A and B was a urea, efficacy values slightly exceeded those with a thiourea linker in the carbonyl-containing THQ systems 3a-g. In contrast, when Ring A possessed the 1,2,2,4,4-pentamethyl-3-hydroxytetrahydroquinolin-6-yl unit (4a-f, series 4), very modest potency and efficacy was observed. Model compound 5, an exact N-methyl THQ analog of SHetA2, demonstrated less potency (IC 4.5 μM), but improved efficacy (91.7%). Modeling studies were performed to rationalize the observed results.
SHetA2（NSC 721689）是我们的主要的 Flex-Het 抗癌药物，由噻吩并[2,3-b]吡啶（环 A）和 4-硝基苯基（环 B）通过硫脲桥连接而成。在这项工作中，我们合成了一系列新的类似物，这些类似物具有四氢喹啉（THQ，环 A）单元，通过脲或硫脲连接子连接到 4-取代的苯基（环 B）。相对于 SHetA2，我们根据与 mortalin 的结合亲和力和对 A2780 卵巢癌细胞的抑制作用对它们进行了评估。其中六种衍生物的疗效与 SHetA2 相当或超过了 SHetA2。缺乏环 A 氮上的甲基和相邻碳上的偕二甲基的化合物 1a-d（系列 1）仅显示出微弱的活性。1a 的季铵化 N，N-二甲基碘盐类似物盐 2 在研究的细胞系中也仅具有适度的生长抑制作用。具有 C3 酮和 N-甲基取代环 A 中硫的系列 3 化合物最为成功。化合物 3a[环 A=1,2,2,4,4-五甲基-3-氧代-1,2,3,4-四氢喹啉-6-基；脲连接子；环 B=4-硝基苯基]的效力稍低（IC 3.8 μM），但疗效（94.8%）优于 SHetA2（IC 3.17 μM，疗效 84.3%）。此外，还评估了 3c 和 3d（脲和硫脲连接子，分别；环 B=4-（三氟甲基）苯基）和 3e 和 3f（脲和硫脲连接子，分别；环 B=4-（三氟甲氧基）苯基），因为这些化合物具有具有氢键能力的吸电子基团。所有这些都表现出良好的活性。与 SHetA2 相比，化合物 3c 和 3e 的效力和疗效均有所提高。一般来说，当环 A 和 B 之间的连接基团是脲时，在含有羰基的 THQ 系统 3a-g 中，疗效值略高于含硫脲的连接体。相比之下，当环 A 具有 1,2,2,4,4-五甲基-3-羟基四氢喹啉-6-基单元（4a-f，系列 4）时，观察到的效力和疗效非常低。模型化合物 5 是 SHetA2 的精确 N-甲基 THQ 类似物，其效力（IC 4.5 μM）较低，但疗效（91.7%）提高。进行了建模研究以合理化观察到的结果。
