Design, Synthesis And Evaluate Of Mek Inhibitors

The mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK/ERK) of the RAS-RAF-MEK-MAPK/ERK has emerged as the crucial route from extracellular signal to intra-cellular. In this signaling pathway, ERK, the substrate of MEK could only be activated by MEK, while MEK is wildly known as the unique substrate of RAF as well. Therefore, Mitogen-activated and extracellular signal regulated kinase kinase (MEK) plays an important role in RAS-RAF-MEK-MAPK/ERK signaling pathway.As MAPK/ERK cascade is a key intracellular signaling pathway involved in regulating mammalian cell proliferation, division, migration and apoptosis and closed related to tumor genesis and spread, MEK, the crucial member, attracted increasing attentions and became a key target of developing anti-cancer drugs.There are two MEK homologs, MEK1and MEK2with their molecular weight being44kD and45kD,respectively, which are80%amino-acid identical. They have very similar three-dimensional structures and are similarly targeted by known inhibitorsThe crystal structures of complexes of the ATP noncompetitive MEK inhibitors, ATP and Mg2+with MEK protein demonstrated that the binding region of the ATP noncompetitive MEK inhibitor to MEK1was a unique hydrophobic pocket, which specifically exist in MEK. Such trait contributes to the commendable selectivity of the noncompetitive MEK inhibitor.Up to date,11ATP noncompetitive MEK1/2inhibitors have entered to clinical studies or are undergoing preclinical trial evaluations. Among them, N-aryl anthranilic acids are the novel ATP noncompetitive MEK inhibitors and have good pharmacological activity, pharmacokinetic properties, tolerability, and safty.According to the initial established structure-activity relationship and pharmacokinetics of the MEK inhibitors, we chose PD198306, the ATP noncompetitive MEK inhibitors as the leading compound, and designed two series of compounds with novel structure by using classic drug design method with the expectation of acquiring highly antitumor activity compounds. Consequently,24target compounds were synthesezied and the structures of them are identified by1H-NMR、19F-NMR and MS. I series compounds Ⅱ series compoundsThe protocol for synthesis of I series compounds is listed below: tetrafluorobenzoic acid was used to synthesized2,3,4,5-tetrafluorobenzonitrile through the ractions of methyl esterification, ammonolysis, dehydration, condensation and hydrolysis in turn. Then2,3,4,5-tetrafluorobenzonitrile was condensated with substituted2-amino-pyridine to yield the intermediates3,4,5-trifluoro-2-(substitutive-pyridin-2-ylamino)benzoic acid, which was uesd to prepared3,4,5-trifluoro-2-(substituted pyridin-2-ylamino)benzaldehyde through reduction and oxidation. Finally,3,4,5-trifluoro-2-(substitutive pyridin-2-ylamino)benzaldehyde were reacted with various of amine oxides yielding the targeted compounds.The protocol for synthesis of Ⅱ series compounds is listed below:2,3,4,5-tetrafluorobenzonitrile was prepared by using ttetrafluorobenzoic acid as our starting material, through methyl esterification, ammonolysis, dehydration, condensation and hydrolysis. Then2,3,4,5-tetrafluorobenzonitrile was condensated with substituted2-amino-pyridine to yield the intermediates3,4,5-trifluoro-2-(substituted pyridin-2-ylamino)benzoic acid.The obtained intermediates were reacted with various of amines, which were prepared by ourselves, to yield the target compounds.The Surface Plasma Research (SPR) method was used to test the binding activity of the synthesezied compounds to MEK-1protein. The result showed the binding affinity of8compounds’(LN2-12、LN3-5. LN3-17. LN5-33、LN3-23、LN5-13、LN5-7. LN3-21) was stronger than that of the positive-control drug PD198306. The antitumor activities screening tesed on cell line are under going.