National Pharmaceutical Teaching Laboratory Center, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
Eur J Med Chem. 2020 Jun 15;196:112271. doi: 10.1016/j.ejmech.2020.112271. Epub 2020 Apr 9.
A series of hybrids of MEK inhibitor and nitric oxide donor have been designed and synthesized. Compound 18h [4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy) propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide] was proven to be more potent than the clinical compound RO5126766 in MDA-MB-231 cells. Compound 18h can significantly reduce the levels of pMEK and pERK, induce cell apoptosis in MDA-MB-231 cells, and release NO in cells efficiently, suggesting that these hybrids, while displaying the properties of both MEK inhibitors and NO donors have a mechanism of action different from that of MEK inhibitors and NO donors. Thus, we are able to report a series of multitarget hybrids with better antitumor potency than a known MEK inhibitor and NO donor.
已设计并合成了一系列 MEK 抑制剂和一氧化氮供体的杂合物。化合物 18h [4-(3-((3-(2-氟-3-((N-甲磺酰基)氨基)苄基)-4-甲基-2-氧代-2H-色烯-7-基)氧基)丙氧基)-3-(苯基磺酰基)-1,2,5-恶二唑 2-氧化物] 被证明比临床化合物 RO5126766 在 MDA-MB-231 细胞中更有效。化合物 18h 可显著降低 pMEK 和 pERK 的水平，诱导 MDA-MB-231 细胞凋亡，并有效释放细胞中的 NO，表明这些杂合物虽然具有 MEK 抑制剂和 NO 供体的特性，但作用机制与 MEK 抑制剂和 NO 供体不同。因此，我们能够报告一系列具有比已知 MEK 抑制剂和 NO 供体更好的抗肿瘤活性的多靶点杂合物。
