五元杂环共轭 4-异丙基间苯二酚骨架苯甲酰胺的开环作为 HSP90 抑制剂，抑制体内外肿瘤生长。
Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo.
机构信息
School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan; Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan.
Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
出版信息
Eur J Med Chem. 2021 Jul 5;219:113428. doi: 10.1016/j.ejmech.2021.113428. Epub 2021 Apr 6.
A series of ring-opened dihydroxybenzamides have been designed and synthesized as heat shock protein 90 inhibitors. One of derivatives, compound 6b ((N-ethyl-2,4-dihydroxy-5-isopropyl-N-(pyridin-3-yl)benzamide)) demonstrated remarkable antiproliferative activity against in human KRAS mutant A549 and EGFR T790 M mutant H1975 lung cancer cell lines with GI values of 0.07 and 0.05 μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI = 0.09 μM), liver Hep3B (GI = 0.20 μM) and breast MDA-MB-231 (GI = 0.09 μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC of 110.18 nM in HSP90α inhibitory activity, slightly better than reference compound 1 (17-AAG, IC = 141.62 nM) and achieves the degradation of multiple HSP90 client proteins in a dose- and time-dependent manner and downstream signaling of Akt in a concentration- and time-dependent manner in the human A549 lung cancer cell line. In the Boyden chamber assay, compound 6b can efficiently inhibit the migration of A549 cells when compared to the reference compound 1. It also induce significant activity through the apoptotic pathway. Treatment with 6b showed no vision toxicity (IC > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC and has no effect in hERG test. In a bidirectional Caco-2 permeability assay, compound 6b was classified as a highly permeable compound which is not a substrate of efflux transporters. In a pharmacokinetic study in rats, 6b showed an F = 17.8% of oral bioavailability. The effect of metabolic stability of compound 6b in human hepatocytes showed a T of 67.59 min. Compound 6b (50 mg/kg, po, daily) exhibits antitumor activity with a 72% TGD (tumor growth delay) in human A549 lung xenograft. The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer.
一系列开环二羟基苯甲酰胺已被设计和合成作为热休克蛋白 90 抑制剂。其中一种衍生物，化合物 6b（（N-乙基-2,4-二羟基-5-异丙基-N-（吡啶-3-基）苯甲酰胺））对人 KRAS 突变 A549 和 EGFR T790M 突变 H1975 肺癌细胞系具有显著的增殖抑制活性，GI 值分别为 0.07 和 0.05 μM。它还对其他癌细胞系具有活性，例如结直肠 HCT116（GI = 0.09 μM）、肝 Hep3B（GI = 0.20 μM）和乳腺癌 MDA-MB-231（GI = 0.09 μM），并且在正常细胞系中没有毒性证据。化合物 6b 在 HSP90α 抑制活性中具有 110.18 nM 的 IC，略优于参考化合物 1（17-AAG，IC = 141.62 nM），并以剂量和时间依赖的方式实现了多种 HSP90 客户蛋白的降解，并以浓度和时间依赖的方式在人 A549 肺癌细胞系中实现了 Akt 的下游信号。在 Boyden 室测定中，与参考化合物 1 相比，化合物 6b 可有效抑制 A549 细胞的迁移。它还通过凋亡途径诱导显著的活性。与 AUY922（3a）相比，化合物 6b 在 661w 光感受器细胞中显示出无明显的视觉毒性（IC > 10 μM），IC 值为 0.04 μM，并且在 hERG 试验中没有影响。在双向 Caco-2 渗透性测定中，化合物 6b 被分类为高渗透性化合物，不是外排转运体的底物。在大鼠的药代动力学研究中，化合物 6b 的口服生物利用度 F 为 17.8%。化合物 6b 在人肝细胞中的代谢稳定性研究表明 T 为 67.59 分钟。化合物 6b（50mg/kg，po，每日）在人 A549 肺癌异种移植中表现出 72%的 TGD（肿瘤生长延迟）的抗肿瘤活性。化合物 6b 与 afatinib 联合口服给药，在肺 H1975 异种移植模型中显示出 67.5%的 TGI 肿瘤生长抑制作用。因此，化合物 6b 是进一步开发用于治疗肺癌的潜在药物的先导化合物。
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