2-氧代-N-芳基-1,2,3,4-四氢喹啉-6-磺酰胺作为肿瘤细胞特异性丙酮酸激酶 M2 同工酶的激活剂。
2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase.
机构信息
NIH Chemical Genomics Center, NIH Center for Translational Therapeutics, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
出版信息
Bioorg Med Chem Lett. 2011 Nov 1;21(21):6322-7. doi: 10.1016/j.bmcl.2011.08.114. Epub 2011 Sep 14.
Abstract
Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described.
摘要
与正常分化细胞相比，癌细胞的代谢调控发生了改变，以支持生物合成，而丙酮酸激酶（PKM2）的 M2 同工酶的表达在这种合成代谢中起着重要作用。虽然 M1 同工酶是一种高活性酶，但剪接的 M2 变体活性显著降低，在肿瘤中表达。虽然降低丙酮酸激酶活性促进合成代谢的确切机制尚不清楚，但据推测，PKM2 的激活水平与 PKM1 相似可能会促进一种不利于细胞增殖的代谢程序。在这里，我们报告了基于 2-氧代-N-芳基-1,2,3,4-四氢喹啉-6-磺酰胺支架的一系列 PKM2 激活剂中的第三个化学型。描述了合成、结构活性关系、选择性和显著的物理化学性质。
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