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| 題名: | Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo |
| 作者: | 劉宜旻
Yi-Min Liu, Huang-Ju Tu, Chueh-Heng Wu, Mei-Jung Lai, Shu-Chieh Yu, Min-Wu Chao, Yi-Wen Wu, Che-Ming Teng, Shiow-Lin Pan, Jing-Ping Liou |
| 貢獻者: | 藥學系藥物科學學科 |
| 關鍵詞: | Keywords: Ring-opening;Heat shock protein 90 inhibitors;Lung cancer |
| 日期: | 2021-07 |
| 上傳時間: | 2025-03-28 10:25:05 (UTC+8) |
| 摘要: | Abstract: 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 GI50 values of 0.07 and 0.05?μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI50?=?0.09?μM), liver Hep3B (GI50?=?0.20?μM) and breast MDA-MB-231 (GI50?=?0.09?μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC50 of 110.18?nM in HSP90α 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?μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04?μM 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 T1/2 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. |
| 關聯: | European Journal of Medicinal Chemistry, Volume 219, 2021, 113428 |
| 描述: | 【112 新聘】臺北醫學大學教師升等專門著作
職別：專任
送審等級：副教授
著作送審 |
| 資料類型: | article |
| 顯示於類別: | [教師升等送審著作] 112
[藥學系] 期刊論文
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