Key Laboratory of Saline-Alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education, College of Life Sciences, Northeast Forestry University, Harbin 150040, China.
Changchun Institute of Biological Products Co., Ltd., Changchun 130011, China.
Molecules. 2023 Jul 28;28(15):5715. doi: 10.3390/molecules28155715.
Betulinic acid (BA) and betulin (BE) are naturally pentacyclic triterpenes with documented biological activities, especially antitumor and anti-inflammatory activity. However, their bioavailability in vivo is not satisfactory in terms of medical applications. Thus, to improve the solubility and bioavailability so as to improve the efficacy, 28-O-succinyl betulin (SBE), a succinyl derivative of BE, was synthesized and its solubility, in vitro and in vivo anti-tumor activities, the apoptosis pathway as well as the pharmacokinetic properties were investigated. The results showed that SBE exhibited significantly higher solubility in most of the tested solvents, and showed a maximum solubility of 7.19 ± 0.66 g/L in -butanol. In vitro and in vivo anti-tumor activity assays indicated both BA and SBE exhibited good anti-tumor activities, and SBE demonstrated better potential compared to BA. An increase in the ratio of Bad/Bcl-xL and activation of caspase 9 was found in SBE treated Hela cells, suggesting that the intrinsic mitochondrial pathway is involved in SBE induced apoptosis. Compared with BA, SBE showed much-improved absorption and bioavailability in pharmacokinetic studies.
白桦脂酸（BA）和白桦脂醇（BE）是具有文献记载的生物活性的天然五环三萜类化合物，特别是具有抗肿瘤和抗炎活性。然而，就医学应用而言，它们在体内的生物利用度并不令人满意。因此，为了提高其溶解度和生物利用度，从而提高疗效，我们合成了白桦脂醇的琥珀酰衍生物 28-O-琥珀酰基白桦脂酸（SBE），并研究了其溶解度、体外和体内抗肿瘤活性、细胞凋亡途径以及药代动力学特性。结果表明，SBE 在大多数测试溶剂中表现出显著更高的溶解度，在正丁醇中最大溶解度为 7.19±0.66 g/L。体外和体内抗肿瘤活性试验表明，BA 和 SBE 均表现出良好的抗肿瘤活性，且 SBE 比 BA 具有更好的潜力。在 SBE 处理的 Hela 细胞中发现 Bad/Bcl-xL 比值增加和 caspase 9 激活，表明内在的线粒体途径参与了 SBE 诱导的细胞凋亡。与 BA 相比，SBE 在药代动力学研究中表现出明显改善的吸收和生物利用度。
