Ruan Zhipeng, Yong Jianping, Li Le, Lu Canzhong, Olatunde Olagoke Zacchaeus
School of Pharmacy and Medical Technology, Putian University, Putian, Fujian, China.
Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine (Putian Univesity), Fujian Province University, Fujian, China.
Curr Pharm Des. 2025;31(31):2537-2545. doi: 10.2174/0113816128391868250430081054.
This study aimed to design and synthesize new ferrocene derivatives for the development of potent anticancer drugs.
Cancer is a major cause of death globally. Some small-molecule anticancer drugs have been used in clinics for the treatment of cancer, and several candidates are in different phases of clinical trials. However, cancer chemotherapy is still highly inadequate due to the side effects of the clinical drugs. Thus, developing novel anticancer drugs is essential.
Firstly, we synthesized the R-substituted benzaldoxime intermediates (2a-2s) using R-substituted benzaldehyde (1a-1s) and hydroxylamine hydrochloride. Then, the target compounds (3a-3s) were synthesized using ferrocene carboxylic acid and R-substituted benzaldoxime intermediates (2a-2s) as starting materials, and using DCC and DMAP as catalysts. The purity of the target compounds was determined by HPLC, and their structures were characterized using NMR, SC-XRD, and HR-ESIMS. Subsequently, the preliminary in vitro cytotoxicity against HeLa, A549, and A2780 cell lines was evaluated using MTT assay.
The results showed that compound 3a exhibited cytotoxicity against both HeLa and A549 cancer cell lines with IC values of 0.691 and 0.876 mM, respectively. Compound 3k showed potent cytotoxicity against HeLa cell lines with an IC value of 0.097 mM, compounds 3n and 3o exhibited potent cytotoxicity against three cancer cell lines, compound 3q showed potent cytotoxicity against HeLa cell lines with an IC value of 0.175 mM, while compound 3s exhibited potent cytotoxicity against HeLa and A549 cell lines with IC values of 0.470 and 0.298 mM, respectively.
In this work, 19 new ferrocene derivatives containing R-substituted benzaldoxime moieties (3a-3s) were synthesized and their structures were confirmed. Their cytotoxicity against HeLa, A549, and A2780 cell lines was tested, and the results showed that several compounds exhibited potent cytotoxicity against the tested cancer cell lines. This work developed a variety of ferrocene compounds, providing lead compounds based on ferrocene pharmacophore for the development of anticancer drugs.
本研究旨在设计并合成新的二茂铁衍生物，用于开发高效抗癌药物。
癌症是全球主要的死亡原因。一些小分子抗癌药物已在临床上用于癌症治疗，还有几种候选药物正处于不同阶段的临床试验中。然而，由于临床药物的副作用，癌症化疗仍然存在很大不足。因此，开发新型抗癌药物至关重要。
首先，我们使用R-取代苯甲醛（1a - 1s）和盐酸羟胺合成了R-取代苯甲醛肟中间体（2a - 2s）。然后，以二茂铁羧酸和R-取代苯甲醛肟中间体（2a - 2s）为原料，使用二环己基碳二亚胺（DCC）和4-二甲氨基吡啶（DMAP）作为催化剂，合成了目标化合物（3a - 3s）。通过高效液相色谱法（HPLC）测定目标化合物的纯度，并使用核磁共振（NMR）、单晶X射线衍射（SC-XRD）和高分辨电喷雾电离质谱（HR-ESIMS）对其结构进行表征。随后，使用噻唑蓝比色法（MTT法）评估了目标化合物对人宫颈癌HeLa细胞系、人肺癌A549细胞系和人卵巢癌A2780细胞系的初步体外细胞毒性。
结果表明，化合物3a对HeLa和A549癌细胞系均表现出细胞毒性，IC值分别为0.691和0.876 mM。化合物3k对HeLa细胞系表现出强效细胞毒性，IC值为0.097 mM；化合物3n和3o对三种癌细胞系均表现出强效细胞毒性；化合物3q对HeLa细胞系表现出强效细胞毒性，IC值为0.175 mM；而化合物3s对HeLa和A549细胞系均表现出强效细胞毒性，IC值分别为0.470和0.298 mM。
在本研究中，合成了19种含有R-取代苯甲醛肟基团的新型二茂铁衍生物（Compound 3a - 3s），并确认了其结构。测试了它们对HeLa、A549和A2780细胞系的细胞毒性，结果表明几种化合物对测试的癌细胞系表现出强效细胞毒性。本研究开发了多种二茂铁化合物，为基于二茂铁药效团的抗癌药物开发提供了先导化合物。
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