Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 Ciudad de México, Mexico.
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, 07000 Ciudad de México, Mexico.
Bioorg Chem. 2020 Sep;102:104080. doi: 10.1016/j.bioorg.2020.104080. Epub 2020 Jul 7.
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 (IC = 21.54 nM) and (R)-4m (IC = 10.81 nM) exhibited better inhibitory activities than TSA (IC = 28.32 nM). These results suggested that 2,6-DKPs derivatives may be promising anticancer agents for further biological studies.
二酮哌嗪（DKP）因其在治疗多种疾病（包括癌症）方面的生物特性，已被视为合成方面的一个重要支架。在这项工作中，通过亲核取代和分子内环化反应合成了两个新型的手性 2,6-DKP 系列，它们来源于α-氨基酸。所有化合物均与组蛋白去乙酰化酶 8（HDAC8）对接，HDAC8 是开发抗癌药物的一个有前途的靶点。这些化合物以类似于 Trichostatin A（TSA）的方式结合到 HDAC8 的活性部位，TSA 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取代基的类型对结合模式起着重要作用。HDAC8-配体复合物的吉布斯自由能和离解常数值表明，化合物 (S)-4hBn、(S)-4m、(R)-4h 和 (R)-4m 比 TSA 更稳定且与 HDAC8 亲和力更强。在体外评估了 4a、(S)-4h、(S)-和 (R)-4(g, l, m) 对 HDAC8 的抑制活性。发现化合物 (R)-4g（IC=21.54 nM）和 (R)-4m（IC=10.81 nM）的抑制活性优于 TSA（IC=28.32 nM）。这些结果表明，2,6-DKP 衍生物可能是有前途的抗癌药物，值得进一步进行生物学研究。
