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Synthesis, docking study and inhibitory activity of 2,6-diketopiperazines derived from α-amino acids on HDAC8.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-07-07 , DOI: 10.1016/j.bioorg.2020.104080
Flor Paulina Garrido González 1 , Teresa Mancilla Percino 1
Affiliation  

Diketopiperazines (DKPs) have been regarded as an important scaffold from the viewpoint of synthesis due to their biological properties for the treatment of several diseases, including cancer. In this work, two novel series of enantiomeric 2,6-DKPs derived from α-amino acids were synthesized through nucleophilic substitution and intramolecular cyclization reactions. All the compounds were docked against histone deacetylase 8 (HDAC8), which is a promising target for the development of anticancer drugs. These compounds bound into the active site of HDAC8 in a similar way to Trichostatin A (TSA), which is an HDAC8 inhibitor. This study showed that the conformation of the 2,6-DKP ring, stereochemistry, and the type of substituent on the chiral center had an important role in the binding modes. The Gibbs free energies and dissociation constants values of HDAC8-ligand complexes showed that compounds (S)-4hBn, (S)-4m, (R)-4h, and (R)-4m were more stable and affine towards HDAC8 than TSA. The inhibitory activities of 4a, (S)-4h, (S)- and (R)-4(g, l, m) were evaluated in vitro on HDAC8. It was found that compounds (R)-4g (IC50 = 21.54 nM) and (R)-4m (IC50 = 10.81 nM) exhibited better inhibitory activities than TSA (IC50 = 28.32 nM). These results suggested that 2,6-DKPs derivatives may be promising anticancer agents for further biological studies.



中文翻译:

衍生自α-氨基酸的2,6-二酮哌嗪对HDAC8的合成,对接和抑制活性。

从合成的观点来看,二酮哌嗪(DKP)由于其用于治疗包括癌症在内的多种疾病的生物学特性而被认为是重要的支架。在这项工作中,通过亲核取代和分子内环化反应合成了来自α-氨基酸的两个新的对映异构体2,6-DKP。所有化合物都与组蛋白脱乙酰基酶8(HDAC8)对接,这是开发抗癌药物的有希望的目标。这些化合物以与Trichostatin A(TSA)类似的方式结合到HDAC8的活性位点,后者是一种HDAC8抑制剂。这项研究表明2,6-DKP环的构象,立体化学和手性中心的取代基类型在结合模式中起着重要作用。小号) - 4hBn,(小号) - 4米,(- [R )- 4H,和(- [R )- 4米更加稳定和仿射朝向HDAC8比TSA。的抑制活性4a中,(小号) - 4H,(小号) -和(- [R )- 4)的评价在体外对HDAC8。发现化合物(R-4g(IC 50  = 21.54 nM)和(R-4m(IC50  = 10.81 nM)表现出比TSA更好的抑制活性(IC 50  = 28.32 nM)。这些结果表明2,6-DKPs衍生物可能是有前途的抗癌药物,用于进一步的生物学研究。

更新日期:2020-07-17
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