Alam Mohammad Sayed, Lee Dong-Ung
Department of Chemistry, Jagannath University, Dhaka 1100, Bangladesh.
Division of Bioscience, Dongguk University, Gyeongju 780-714, Republic of Korea.
Med Chem. 2022;19(1):47-63. doi: 10.2174/1573406418666220427105041.
The aim of the study was to search for new anticancer agents as TRKA inhibitors.
A series of new salicylic acid hydrazide hydrazones were synthesized and evaluated for their in vitro anticancer activities against lung (A549), ovarian (SK-OV-3), skin (SK-MEL-2), and colon (HCT15) cancer cell lines, and tropomyosin receptor kinase A (TRKA) inhibitory activities.
In this study, we focused on the synthesis and anticancer properties evaluation of salicylic acid hydrazide hydrazones as TRKA inhibitors. The in vitro anticancer activities of hydrazone analogs were measured against four cancer cell lines, and the TRKA inhibitory properties were investigated using an enzyme assay to determine their modes of action. In silico molecular docking was conducted using the crystal structure of the TRKA receptor to study the interactions and modes of binding at its active site, and ligand-based target predictions were used to identify putative secondary enzymatic targets of the synthesized compounds. Additionally, pharmacokinetic properties, toxicity effects, and drug scores of the studied molecules were also assessed.
A series of hydrazide hydrazones were prepared by means of a facile and straight-forward two-step reaction under soft reflux conditions from a methyl ester of substituted aromatic acids and hydrazine hydrate followed by the condensation with substituted aldehydes. In vitro cytotoxic properties of the synthesized compounds were screened against four human cancer cells using the SRB (sulforhodamine-B) colorimetric method. The TRKA inhibitory activity was measured by enzymatic assay. In silico ADME, drug score properties, docking studies, and ligand-based target prediction analyses were performed using Osiris Cheminformatics and AutoDock Vina, and SwissTargetPrediction bioinformatics software.
In vitro bioassays revealed that compound 6 exhibited the most potent broad-spectrum anticancer activities with IC values of 0.144, <0.001, 0.019, and 0.022 μM against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, respectively, followed by compounds 11, 3a, and 9. In TRKA inhibitory assays, compounds 3e and 11 demonstrated the highest potency with IC values of 111 and 614 nM, respectively. The results of docking studies on 3e and 11 with the active site of the TRKA receptor revealed that both compounds interacted as previously reported TRKA inhibitors with high docking scores.
New salicylic acid hydrazide hydrazones were synthesized, and the most active compounds exhibited significant anticancer properties against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, suggesting to be good candidates for in vivo studies. The results obtained in the present study would help in the design and preparation of new hydrazidehydrazone analogs as potential TRKA inhibitors for cancer treatment.
本研究旨在寻找新型抗癌药物作为TRKA抑制剂。
合成了一系列新型水杨酰肼腙，并评估了它们对肺癌（A549）、卵巢癌（SK-OV-3）、皮肤癌（SK-MEL-2）和结肠癌（HCT15）细胞系的体外抗癌活性以及对原肌球蛋白受体激酶A（TRKA）的抑制活性。
在本研究中，我们专注于水杨酰肼腙作为TRKA抑制剂的合成及抗癌特性评估。采用比色法测定了腙类似物对四种癌细胞系的体外抗癌活性，并通过酶促试验研究了其TRKA抑制特性以确定其作用方式。利用TRKA受体的晶体结构进行了计算机辅助分子对接研究，以探讨其在活性位点的相互作用和结合模式，并基于配体进行靶点预测以识别合成化合物潜在的二级酶靶点。此外，还评估了所研究分子的药代动力学性质、毒性作用和药物评分。
通过简便直接的两步反应，在温和回流条件下，由取代芳香酸甲酯与水合肼反应，随后与取代醛缩合制备了一系列酰肼腙。采用磺酰罗丹明B（SRB）比色法筛选合成化合物对四种人类癌细胞的体外细胞毒性。通过酶促试验测定TRKA抑制活性。使用Osiris化学信息学软件、AutoDock Vina软件和SwissTargetPrediction生物信息学软件进行了计算机辅助的药物代谢及药物动力学（ADME）、药物评分性质、对接研究和基于配体的靶点预测分析。
体外生物测定表明，化合物6表现出最有效的广谱抗癌活性，对A549、SK-OV-3、SK-MEL-2和HCT15癌细胞的IC值分别为0.144、<0.001、0.019和0.022 μM，其次是化合物11、3a和9。在TRKA抑制试验中，化合物3e和11表现出最高活性，IC值分别为111和614 nM。对3e和11与TRKA受体活性位点的对接研究结果表明，这两种化合物均如先前报道的TRKA抑制剂一样相互作用，对接分数较高。
合成了新型水杨酰肼腙，其中活性最高的化合物对A549、SK-OV-3、SK-MEL-2和HCT15癌细胞表现出显著的抗癌特性，表明它们有望成为体内研究的良好候选药物。本研究所得结果将有助于设计和制备新型酰肼腙类似物，作为潜在的TRKA抑制剂用于癌症治疗。
