Hybrids of MEK inhibitor and NO donor as multitarget antitumor drugs.

Chao Wang, Dandan Xi, Han Wang, Yan Niu, Lei Liang, Fengrong Xu, Yihong Peng, Ping Xu

European journal of medicinal chemistry 2020 Jun 15

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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. Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Citation

Chao Wang, Dandan Xi, Han Wang, Yan Niu, Lei Liang, Fengrong Xu, Yihong Peng, Ping Xu. Hybrids of MEK inhibitor and NO donor as multitarget antitumor drugs. European journal of medicinal chemistry. 2020 Jun 15;196:112271