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Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2018-01-08 , DOI: 10.1111/cbdd.13156
Ting-Jian Zhang 1 , Song-Ye Li 1 , Wei-Yan Yuan 1 , Yi Zhang 1 , Fan-Hao Meng 1
Affiliation  

A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives (1d and 1i) and the L/D‐tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC50 = 3.0 μm) and the D‐phenylalanine derivative 1i (IC50 = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50 = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.

中文翻译:

N-(9,10-蒽醌-2-羰基)氨基酸衍生物作为黄嘌呤氧化酶抑制剂的设计,合成和分子对接研究

设计并合成了一系列N-(9,10-蒽醌-2-羰基)氨基酸衍生物(1a-j)作为新型黄嘌呤氧化酶抑制剂。其中,L / D-苯丙氨酸衍生物(1d1i)和L / D-色氨酸衍生物(1e1j)在微摩尔水平效力上是有效的。特别地,大号-苯丙氨酸衍生物1D(IC 50  = 3.0μ)和d -苯丙氨酸衍生物1I(IC 50 = 2.9μ)给出的最高效力和均比阳性对照别嘌醇(IC更有效50  = 8.1μ)。SAR的初步分析指出,芳香氨基酸片段(例如苯丙氨酸或色氨酸)对于抑制作用至关重要。的d相比,它的α-氨基酸衍生物呈现等于或更大的效力大号-对映体; 9,10-蒽醌部分受到抑制。分子模拟为黄嘌呤氧化酶活性口袋中的化合物1d1i提供了合理的结合模型。结果,化合物1d1i 可能是有前途的铅化合物,有待进一步研究。
更新日期:2018-01-08
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