Department of Chemistry, Oklahoma State University, Stillwater, OK, 74078, USA.
Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma, Health Sciences Center, Oklahoma City, OK, 73104, USA.
Eur J Med Chem. 2018 Oct 5;158:720-732. doi: 10.1016/j.ejmech.2018.09.036. Epub 2018 Sep 14.
Five series of chromans with urea and thiourea linkers connecting a chroman unit (ring A) and a 4-substituted benzene unit (ring B) have been prepared and evaluated relative to SHetA2 (NSC 721689) for activity against the human A2780 ovarian cancer cell line. The lead compound SHetA2 had a sulfur in place of the oxygen in ring A and a thiourea linker to ring B. The 2-Me-4-Me series (two sets of geminal dimethyl groups at C2 and at C4 on the ring A unit) permitted direct comparison with SHetA2. Ring B in this series was evaluated with specific functional groups at C4 on the ring, including NO, COEt, CF, OCF, CN and SONH. The 2-H-4-Me series (only one geminal dimethyl group at the C4 position on ring A) permitted structure-activity relationship analysis to assess the importance of the hydrophobic geminal dimethyl groups on ring A to the activity of SHetA2. The remaining three series 2-Et-4-Me, 2-Me-4-Et and 2-Et-4-Et (ring A methyl groups replaced with ethyls at C2, at C4 and at both C2 and C4, respectively) offered the opportunity to modulate the hydrophobicity of the chroman moiety. Additionally, in all these series, the influence of a urea versus a thiourea linker was also investigated. The results of these modifications are summarized below. The exact analog of SHetA2 with oxygen substituted for sulfur in ring A (2a) showed comparable efficacy but a significantly lower IC against the ovarian cancer cell line. The urea linked analogs bearing CN, CF and OCF at C4 of ring B (3c,d and f) showed greater efficacy than SHetA2, but also had lower IC values. Removing the geminal dimethyl group at C2 (4a-c, 5a-c) caused a significant lowering of the efficacy and percent growth inhibition, indicating that the hydrophobic geminal dimethyl group at C2 in ring A is crucial for activity. Finally, replacing the geminal dimethyl groups with geminal diethyls on ring A in the urea derivatives gave 6b-c, 7c-d and 8b, all of which outperformed SHetA2 with respect to efficacy and IC. The results for compounds 4-8 are in concurrence with modeling studies, which predicted that greater hydrophobicity in ring A would be beneficial. Binding energies were determined for compounds docked in silico to mortalin, the protein identified as a receptor of SHetA2. The urea linker promoted activity comparable to or, in some cases, greater than compounds with a thiourea linker. Several compounds achieved 94% efficacy and an IC of 2 μM, which were better than SHetA2 (84%, 3 μM).
已经制备了五个系列的带有脲和硫脲连接体的色满，连接一个色满单元（环 A）和一个 4-取代苯单元（环 B），并相对于 SHetA2（NSC 721689）对人 A2780 卵巢癌细胞系进行了活性评估。先导化合物 SHetA2 在环 A 中有一个硫取代氧，在环 B 中有一个硫脲连接体。2-Me-4-Me 系列（环 A 单元的 C2 和 C4 上有两个偕二甲基）允许与 SHetA2 进行直接比较。该系列中环 B 用环上的特定官能团进行了评估，包括 NO、COEt、CF、OCF、CN 和 SONH。2-H-4-Me 系列（环 A 的 C4 位置只有一个偕二甲基）允许进行构效关系分析，以评估环 A 上的疏水性偕二甲基对 SHetA2 活性的重要性。其余三个系列 2-Et-4-Me、2-Me-4-Et 和 2-Et-4-Et（环 A 的甲基分别用乙基取代 C2、C4 和 C2 和 C4）提供了调节色满部分疏水性的机会。此外，在所有这些系列中，还研究了脲与硫脲连接体的影响。这些修饰的结果总结如下。在环 A 中用硫取代氧的 SHetA2 的精确类似物（2a）显示出相当的功效，但对卵巢癌细胞系的 IC 明显较低。在环 B 的 C4 上带有 CN、CF 和 OCF 的脲连接类似物（3c、d 和 f）显示出比 SHetA2 更高的功效，但也具有更低的 IC 值。去除 C2 上的偕二甲基（4a-c、5a-c）导致功效和生长抑制百分比显着降低，表明环 A 中 C2 上的疏水性偕二甲基对活性至关重要。最后，在脲衍生物中环 A 的偕二甲基用偕二乙基取代，得到 6b-c、7c-d 和 8b，它们在功效和 IC 方面均优于 SHetA2。化合物 4-8 的结果与建模研究一致，预测环 A 中更大的疏水性将是有益的。对在计算机中对接的化合物进行了结合能测定，鉴定出 mortalin 是 SHetA2 的受体。脲连接体促进了与硫脲连接体相比活性相当或在某些情况下更高的活性。几种化合物达到了 94%的功效和 2µM 的 IC，优于 SHetA2（84%，3µM）。
