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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo
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Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo

机译：五元杂环的开环以Hsp90抑制剂在体外和体内抑制肿瘤生长的Hsp90抑制剂的五元杂环缀合的4-异丙基丙烯醛苯甲酰胺。

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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(50) values of 0.07 and 0.05 mu M, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI(50) = 0.09 mu M), liver Hep3B (GI(50) = 0.20 mu M) and breast MDA-MB-231 (GI(50) = 0.09 mu M), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC50 of 110.18 nM in HSP90a inhibitory activity, slightly better than reference compound 1 (17-AAG, IC50 = 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 (IC50 > 10 mu M) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 mu M values of IC50 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-1/2 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. (C) 2021 Published by Elsevier Masson SAS.
机译：设计并合成了一系列开环二羟基苯甲酰胺类热休克蛋白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GI（50）值分别为0.07和0.05μM的人类KRAS突变体A549和EGFR T790 M突变体H1975肺癌细胞株显示出显著的抗增殖活性。在其他癌症细胞系中，如大肠HCT116（GI（50）=0.09μM）、肝脏Hep3B（GI（50）=0.20μM）和乳腺MDA-MB-231（GI（50）=0.09μM）也具有活性，并且在正常细胞系中未显示毒性证据。化合物6b的HSP90a抑制活性的IC50为110.18 nM，略好于对照化合物1（17-AAG，IC50=141.62 nM），并在人A549肺癌细胞系中以剂量和时间依赖的方式降解多个HSP90客户蛋白，并以浓度和时间依赖的方式降解Akt下游信号。在Boyden小室试验中，与对照化合物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IC50值为0.04μM的AUY922（3a）相比，6b处理对661w感光细胞没有视觉毒性（IC50>10μM），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被归类为高渗透性化合物，它不是外排转运体的底物。在大鼠的药代动力学研究中，6b显示F=17.8%的口服生物利用度。化合物6b在人类肝细胞中的代谢稳定性效应显示T-1/2为67.59 min。化合物6b（50 mg/kg，po，每日）在人类A549异种肺移植中显示出抗肿瘤活性，TGD（肿瘤生长延迟）为72%。在H1975异种肺移植模型中，口服6b和阿法替尼的组合显示肿瘤生长抑制率为67.5%。因此，化合物6b是进一步开发治疗肺癌的潜在药物的先导化合物。（c）2021由爱思唯尔马松SAS出版。

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