Design, Synthesis, and Pharmacological Evaluation of First-in-Class Multitarget N-Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors.,ChemMedChem

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Design, Synthesis, and Pharmacological Evaluation of First-in-Class Multitarget N-Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-02-05 , DOI: 10.1002/cmdc.201900716
Daniel A Rodrigues _{1,

2} , Fabiana S Guerra ₃ , Fernanda S Sagrillo ₁ , Pedro de Sena M Pinheiro _{1,

4} , Marina A Alves ₅ , Sreekanth Thota ₁ , Lorrane S Chaves _{1,

4} , Carlos M R Sant'Anna _{1,

6} , Patrícia D Fernandes ₃ , Carlos A M Fraga _{1,

2,

4}

Affiliation

Targeting histone deacetylases (HDACs) and phosphatidylinositol 3-kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, in vitro pharmacological profile, and molecular modeling of a novel class of N-acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer.

中文翻译：

设计，合成和药理学评价一流的多目标N-酰基Ac衍生物作为选择性HDAC6 / 8和PI3Kα抑制剂。

靶向组蛋白脱乙酰基酶（HDACs）和磷脂酰肌醇3-激酶（PI3Ks）是一种非常有前途的癌症治疗方法。该手稿描述了充当HDAC6 / 8和PI3Kα双重抑制剂的新型N-酰基hydr（NAH）衍生物的设计，合成，体外药理学特征和分子模型。对PI3Kα的惊人的选择性可能与活性位点的构象差异有关。细胞研究表明，这些化合物在HDAC6抑制和PI3 / K / AKT / mTOR途径中起作用。选择性抑制HDAC6 / 8和抑制PI3Kα的化合物显示出治疗癌症的潜力。

更新日期：2020-02-18

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