Design, Synthesis, and Evaluation of Inhibitors of Pyruvate Phosphate Dikinase

作者：Wu Chun; Dunaway Mariano Debra; Mariano Patrick S^*

来源：Journal of Organic Chemistry, 2013, 78(5): 1910-1922.

DOI：10.1021/jo3018473

Pyruvate phosphate dikinase (PPDK) catalyzes the phosphorylation reaction of pyruvate that forms phosphoenolpyruvate (PEP) via two partial reactions: PPDK + ATP + P-i -%26gt; PPDK-P + AMP + PPi and PPDK-P + pyruvate(i) -%26gt; PEP + PPDK. Based on its role in the metabolism of microbial human pathogens, PPDK is a potential drug target. A screen of substances that bind to the PPDK ATP-grasp domain active site revealed that flavone analogues are potent inhibitors of the Clostridium symbiosum PPDK. In silico modeling studies suggested that placement of a 3-6 carbon-tethered ammonium substituent at the 3%26apos;- or 4%26apos;-positions of 5,7-dihydroxyflavones would result in favorable electrostatic interactions with the PPDK Mg-ATP binding site. As a result, polymethylene-tethered amine derivatives of 5,7-dihydroxyflavones were prepared. Steady-state kinetic analysis of these substances demonstrates that the 4%26apos;-aminohexyl-5,7-dyhydroxyflavone 10 is a potent competitive PPDK inhibitor (K-i = 1.6 +/- 0.1 mu M). Single turnover experiments were conducted using 4%26apos;-aminopropyl-5,7-dihydroxyflavone 7 to show that this flavone specifically targets the ATP binding site and inhibits catalysis of only the PPDK + ATP + P-i -%26gt; PPDK-P + AMP PP, partial reaction. Finally, the 4%26apos;-aminopbutyl-5,7-dihydroxyflavone 8 displays selectivity for inhibition of PPDK versus other enzymes that utilize ATP and NAD.

• 出版日期2013-3-1