Department of Chemistry, Faculty of Science (Girl's Branch), Al-Azhar University, Nasr City, Cairo, Egypt.
Department of Chemistry, Faculty of Science (Boy's Branch), Al-Azhar University, Nasr City, Cairo, Egypt.
Protein J. 2024 Oct;43(5):949-966. doi: 10.1007/s10930-024-10232-x. Epub 2024 Sep 21.
The synthesis of new agents for cancer treatment persists due to its global lethality. A series of thirteen derivatives, namely salicylic acid-5-sulfohydrazide (SA-SH) analogs, were designed and synthesized from 5-(chlorosulfonyl)-2-hydroxybenzoic acid via nucleophilic substitution reaction with different acid hydrazides, thiocarbohydrazide & thiosemicarbazide scaffolds. Confirmation of the designed derivative's structures employed various spectroscopic techniques (FT-IR and NMR) and elemental analysis. The newly synthesized synthons were evaluated for cytotoxic activity against HepG-2 and HCT-116 cell lines in comparison to Doxorubicin. Notably, SA-SH derivatives (5, 7, 8a, 8b and 11) exhibited significantly higher efficacy against HepG-2 and HCT-116 cell lines than other analogs. Furthermore, compound (8a) demonstrated a superior activity against HepG-2 cell lines with IC values of 3.99 ± 0.2 μM than the reference drug, Doxorubicin, (IC HepG-2 = 4.50 ± 0.2 µM). The molecular docking simulation of the most active SA-SH derivatives and the reference drug doxorubicin into the active site of FGFR4 (fibroblast growth factor receptor, the predominant isoform expressed in human hepatocytes) (PDB ID: 6V9C) proved the usefulness of hybridizing salicylic scaffold with SO and hydrazide moieties as a promising approach in designing new anticancer agents. Finally, ADME and drug-likeness features of the most active compounds compared to positive controls were investigated to increase the success possibilities in clinical trials and they were found to be promising candidates for further investigation and development as drugs.
由于其全球致死率，针对癌症治疗的新药物的合成仍在继续。通过与不同酸酰肼、硫代碳酰肼和硫代缩氨基脲支架的亲核取代反应，从 5-（氯磺酰基）-2-羟基苯甲酸出发，设计并合成了一系列 13 种衍生物，即水杨酸-5-磺酰肼（SA-SH）类似物。采用各种光谱技术（FT-IR 和 NMR）和元素分析对设计的衍生物结构进行了确认。将新合成的缩合试剂与多柔比星（Doxorubicin）比较，评估了对 HepG-2 和 HCT-116 细胞系的细胞毒性活性。值得注意的是，SA-SH 衍生物（5、7、8a、8b 和 11）对 HepG-2 和 HCT-116 细胞系的疗效明显高于其他类似物。此外，化合物（8a）对 HepG-2 细胞系的活性优于参考药物多柔比星（IC HepG-2 = 3.99 ± 0.2 μM），而多柔比星的 IC 值为（IC HepG-2 = 4.50 ± 0.2 μM）。最活跃的 SA-SH 衍生物和参考药物多柔比星与 FGFR4（成纤维细胞生长因子受体，人肝细胞中表达的主要同工型）（PDB ID：6V9C）的活性位点对接的分子模拟证明了将水杨酸支架与 SO 和酰肼部分杂交作为设计新型抗癌药物的有前途的方法的有效性。最后，与阳性对照物相比，研究了最活跃化合物的 ADME 和类药性特征，以增加临床试验成功的可能性，它们被发现是进一步研究和开发为药物的有前途的候选物。
