Bakare Oladapo, Ashendel Curtis L, Peng Hairuo, Zalkow Leon H, Burgess Edward M
Department of Chemistry, Howard University, 525 College Street, Washington, DC 20059, USA.
Bioorg Med Chem. 2003 Jul 17;11(14):3165-70. doi: 10.1016/s0968-0896(03)00267-0.
Mitogen activated protein kinases are of interest as research tools and as therapeutic target for certain physiological disorders. In this study, we found 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone 6 to be a selective inhibitor of MEK1 with an IC(50) of 0.38 microM. An open-chain homologue, 10, showed selective cytotoxicity against renal cancer in the NCI in vitro tumor screening. Structure-activity relationship study of eight compounds showed the cyclic imido-substituted chloro-1,4-naphthoquinone as more potent and selective MEK1 inhibitors than the open chain homologues. The imido-substituted chloro-1,4-naphthoquinones were synthesized in a straightforward fashion by refluxing 2-amino-3-chloro-1,4-naphthoquinone with the appropriate acid chloride or diacyl dichloride.
丝裂原活化蛋白激酶作为研究工具和某些生理紊乱的治疗靶点备受关注。在本研究中，我们发现2-氯-3-(N-琥珀酰亚胺基)-1,4-萘醌6是MEK1的选择性抑制剂，其IC(50)为0.38微摩尔。一种开链同系物10在NCI体外肿瘤筛选中显示出对肾癌的选择性细胞毒性。对八种化合物的构效关系研究表明，环状亚胺取代的氯-1,4-萘醌比开链同系物更有效且更具选择性地抑制MEK1。通过将2-氨基-3-氯-1,4-萘醌与适当的酰氯或二酰二氯回流，以直接的方式合成了亚胺取代的氯-1,4-萘醌。
