利尼伐尼与 2,3-二氯-3,5-二氰基-1,4-苯醌的电荷转移复合物：合成、光谱特征、计算分子建模及在新型 96 孔微量分光光度法测定中的应用。

Charge-Transfer Complex of Linifanib with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone: Synthesis, Spectroscopic Characterization, Computational Molecular Modelling and Application in the Development of Novel 96-microwell Spectrophotometric Assay.

机构信息

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

Medicinal Aromatic and Poisonous Plant Research Centre, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

出版信息

Drug Des Devel Ther. 2021 Mar 12;15:1167-1180. doi: 10.2147/DDDT.S296502. eCollection 2021.

BACKGROUND

Linifanib (LFB) is a multi-targeted receptor tyrosine kinase inhibitor used in the treatment of hepatocellular carcinoma and other types of cancer. The charge-transfer (CT) interaction of LFB is important in studying its receptor binding mechanisms and useful in the development of a reliable CT-based spectrophotometric assay for LFB in its pharmaceutical formulation to assure its therapeutic benefits.

PURPOSE

The aim of this study was to investigate the CT reaction of LFB with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ) and its application in the development of a novel 96-microwell spectrophotometric assay for LFB.

METHODS

The reaction was investigated, its conditions were optimized, the physicochemical and constants of the CT complex and stoichiometric ratio of the complex were determined. The solid-state LFB-DDQ complex was synthesized and its structure was analyzed by UV-visible, FT-IR, and H-NMR spectroscopic techniques, and also by the computational molecular modeling. The reaction was employed in the development of a novel 96-microwell spectrophotometric assay for LFB.

RESULTS

The reaction resulted in the formation of a red-colored product, and the spectrophotometric investigations confirmed that the reaction had a CT nature. The molar absorptivity of the complex was linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9526 and 0.9459, respectively. The stoichiometric ratio of LFB:DDQ was 1:2. The spectroscopic and computational data confirmed the sites of interaction on the LFB molecule, and accordingly, the reaction mechanism was postulated. The reaction was utilized in the development of the first 96-microwell spectrophotometric assay for LFB. The assay limits of detection and quantitation were 1.31 and 3.96 μg/well, respectively. The assay was successfully applied to the analysis of LFB in its bulk and tablets with high accuracy and precision.

CONCLUSION

The assay is simple, rapid, accurate, eco-friendly as it consumes low volumes of organic solvent, and has high analysis throughput.

背景

利尼伐尼（LFB）是一种多靶点受体酪氨酸激酶抑制剂，用于治疗肝癌和其他类型的癌症。LFB 的电荷转移（CT）相互作用在研究其受体结合机制中很重要，并且在开发用于其药物制剂的可靠 CT 分光光度法测定 LFB 方面很有用，以确保其治疗效果。

目的

本研究旨在研究 LFB 与 2,3-二氯-3,5-二氰基-1,4-苯醌（DDQ）的 CT 反应，并将其应用于开发新型 96 微孔分光光度法测定 LFB。

方法

研究了反应条件，优化了反应条件，确定了 CT 络合物的物理化学常数和络合物的化学计量比。通过紫外可见、傅里叶变换红外和 H-NMR 光谱技术以及计算分子建模合成了 LFB-DDQ 固溶体复合物，并分析了其结构。该反应用于开发新型 96 微孔分光光度法测定 LFB。

结果

反应生成红色产物，分光光度研究证实反应具有 CT 性质。络合物的摩尔吸光率与溶剂的介电常数和极性指数呈线性相关；相关系数分别为 0.9526 和 0.9459。LFB:DDQ 的化学计量比为 1:2。光谱和计算数据证实了 LFB 分子上的相互作用位点，并据此提出了反应机制。该反应用于开发第一个 96 微孔分光光度法测定 LFB。测定的检测限和定量限分别为 1.31 和 3.96 μg/孔。该测定法成功地用于 LFB 原料药和片剂的分析，具有很高的准确性和精密度。