College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China; Livzon Pharmaceutical Group Inc., Zhuhai, PR China; National Engineering Research Center for Modernization of Traditional Chinese Medicine, Zhuhai, PR China.
Biomed Pharmacother. 2018 Feb;98:157-164. doi: 10.1016/j.biopha.2017.12.018. Epub 2017 Dec 27.
Crocetin is a natural product possessing extraordinary therapeutic effects for various diseases. However, its extremely low solubility limits its application greatly. Conjugation of organic compounds containing heteroatoms such as N to poor soluble molecules can help the synthesized derivative to form stable hydrogen bonds by lowering the salvation energy, which will improve the solubility of the synthesized compounds. Herein, crocetin was modified by conjugating with piperidyl, diethylin and benzylamine to improve their solubility and bioactivities. In the present study, the conjugation of crocetin with piperidyl, diethylin and benzylamine and their influence on the solubility and the pharmacological effects of crocetin were investigated. With the described strategy, crocetin derivatives were synthesized and their structures were elucidated by H NMR, C NMR and UPLC-MS spectroscopic analysis. The solubility of crocetin and its derivatives were identified. Upon that, the pharmacological effects of the crocetin derivatives on the tumor and inflammation treatment were investigated. It was shown that, in contrast to crocetin, of which, the solubility and pharmacological effects were low and limited, the synthesized compounds have significantly higher solubility and possess broad spectrum of anticancer effects in multiple tumor cell lines, including B16F10, MCF-7, A549 and SKOV3, as well as enhanced anti-inflammation efficacy in macrophage (RAW264.7) without causing cells damage. Conjugation of piperidyl, diethylin and benzylamine with the crocetin was demonstrated to be a highly efficient strategy to improve the solubility of crocetin. The synthesized crocetin derivatives were shown the promising therapeutics for the tumor and inflammation treatment with high safety.
西红花酸是一种具有多种疾病治疗作用的天然产物。然而，其极低的溶解度极大地限制了其应用。将含有杂原子如 N 的有机化合物与难溶性分子结合，可以通过降低溶剂化能帮助合成的衍生物形成稳定的氢键，从而提高合成化合物的溶解度。在此，通过将西红花酸与哌啶、二乙胺和苄胺缀合来修饰西红花酸，以提高其溶解度和生物活性。在本研究中，研究了西红花酸与哌啶、二乙胺和苄胺的缀合及其对西红花酸溶解度和药理作用的影响。采用该方法合成了西红花酸衍生物，并通过 1H NMR、13C NMR 和 UPLC-MS 光谱分析确定了其结构。鉴定了西红花酸及其衍生物的溶解度。在此基础上，研究了西红花酸衍生物对肿瘤和炎症的治疗作用。结果表明，与溶解度和药理作用均较低且有限的西红花酸相比，合成的化合物具有更高的溶解度，对多种肿瘤细胞系（包括 B16F10、MCF-7、A549 和 SKOV3）具有广谱的抗癌作用，并且在不引起细胞损伤的情况下增强了巨噬细胞（RAW264.7）的抗炎作用。证明了将哌啶、二乙胺和苄胺与西红花酸缀合是提高西红花酸溶解度的有效策略。合成的西红花酸衍生物具有良好的抗肿瘤和抗炎治疗潜力，且安全性高。
