Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt.

Objectives: The objective of this work was to identify potent anticancer agents targeting Akt.

Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package.

Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three.

Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

背景：Akt在多种人类癌症中过度表达或激活，包括神经胶质瘤，肺癌，乳腺癌，卵巢癌，胃癌和胰腺癌。Akt的抑制导致细胞凋亡的诱导和肿瘤生长的抑制，因此，人们致力于发现针对Akt的有效抗肿瘤药物。

目的：这项工作的目的是确定针对Akt的有效抗癌药。

方法：合成新的on衍生物，并研究其对5RP7 H-ras癌基因转化的大鼠胚胎成纤维细胞和L929小鼠胚胎成纤维细胞系的细胞毒性作用。此外，使用流式细胞术评估了最具活性的化合物对5RP7细胞系的凋亡作用。还使用比色测定法研究了其对Akt的抑制作用。在计算机对接和吸收，分布，代谢和排泄（ADME）研究中，也使用Schrödinger的Maestro分子建模软件包进行了研究。

结果与讨论：与顺铂相比，发现化合物3a，3d，3g和3j对5RP7细胞有效（IC50值分别<0.97，<0.97、1.13±0.06和<0.97μg/ mL）。 1.87±0.15μg/ mL）。已经确定这四种化合物显着诱导5RP7细胞系中的细胞凋亡。其中，与GSK690693（IC50）相比，N'-亚苄基-2-[（4-（4-甲氧基苯基）嘧啶-2-基）硫代]乙酰肼（3g）显着抑制Akt（IC50 = 0.5±0.08μg/ mL）。 = 0.6±0.05μg/ mL）。对接研究表明，化合物3g对Akt的活性位点显示出良好的亲和力（PDB代码：2JDO）。根据计算机模拟ADME的研究，该化合物还符合Lipinski的5规则和Jorgensen的3规则。

结论：化合物3g是潜在的口服生物利用细胞毒剂和靶向Akt的凋亡诱导剂。