Synthesis and evaluation of (±)-dunnione and its ortho-quinone analogues as substrates for NAD(P)H:quinone oxidoreductase 1 (NQO1). Issue 6 (15th March 2015)

• Record Type: Journal Article
• Authors: Bian, Jinlei; Xu, Lili; Deng, Bang; Qian, Xue; Fan, Jun; Yang, Xiuwen; Liu, Fang; Xu, Xiaoli; Guo, Xiaoke; Li, Xiang; Sun, Haopeng; You, Qidong; Zhang, Xiaojin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 6(2015)
• Page Start: 1244
• Page End: 1248
• Publication Date: 2015-03-15
• Subjects: Natural product -- Dunnione -- NQO1 -- Antitumor -- Reactive oxygen species (ROS); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.057
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Natural product (±)-dunnione (2 ) and its ortho -quinone analogues (3 –8 ) were synthesized and found to be substrates for NQO1. The structure–activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C–H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2 − ) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho -quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling.