Department of Chemistry, Tshwane University of Technology, Private Bag X680, Pretoria, 0001, South Africa.
Department of Biochemistry and Microbiology, Female Cancers Research at Rhodes University (FemCR2U), Makhanda/Grahamstown, 6140, South Africa.
BMC Complement Med Ther. 2023 Sep 11;23(1):316. doi: 10.1186/s12906-023-04137-y.
Stigmasterol is an unsaturated phytosterol that belong to the class of tetracyclic steroids abundant in Rhoicissus tridentata. Stigmasterol is an important constituent since it has shown impressive pharmacological effects such as anti-osteoarthritis, anticancer, anti-diabetic, anti-inflammatory, antiparasitic, immunomodulatory, antifungal, antioxidant, antibacterial, and neuroprotective activities. Furthermore, due to the presence of π system and hydroxyl group, stigmasterol is readily derivatized through substitution and addition reactions, allowing for the synthesis of a wide variety of stigmasterol derivatives.
Stigmasterol (1) isolated from Rhoicissus tridentata was used as starting material to yield eight bio-active derivatives (2-9) through acetylation, epoxidation, epoxide ring opening, oxidation, and dihydroxylation reactions. The structures of all the compounds were established using spectroscopic techniques, NMR, IR, MS, and melting points. The synthesized stigmasterol derivatives were screened for cytotoxicity against the hormone receptor-positive breast cancer (MCF-7), triple-negative breast cancer (HCC70), and non-tumorigenic mammary epithelial (MCF-12 A) cell lines using the resazurin assay.
Eight stigmasterol derivatives were successfully synthesized namely; Stigmasterol acetate (2), Stigmasta-5,22-dien-3,7-dione (3), 5,6-Epoxystigmast-22-en-3β-ol (4), 5,6-Epoxystigmasta-3β,22,23-triol (5), Stigmastane-3β,5,6,22,23-pentol (6), Stigmasta-5-en-3,7-dion-22,23-diol (7), Stigmasta-3,7-dion-5,6,22,23-ol (8) and Stigmast-5-ene-3β,22,23-triol (9). This is the first report of Stigmasta-5-en-3,7-dion-22,23-diol (7) and Stigmasta-3,7-dion-5,6,22,23-ol (8). The synthesized stigmasterol analogues showed improved cytotoxic activity overall compared to the stigmasterol (1), which was not toxic to the three cell lines tested (EC ˃ 250 µM). In particular, 5,6-Epoxystigmast-22-en-3β-ol (4) and stigmast-5-ene-3β,22,23-triol (9) displayed improved cytotoxicity and selectivity against MCF-7 breast cancer cells (EC values of 21.92 and 22.94 µM, respectively), while stigmastane-3β,5,6,22,23-pentol (6) showed improved cytotoxic activity against the HCC70 cell line (EC: 16.82 µM).
Natural products from Rhoicissus tridentata and their derivatives exhibit a wide range of pharmacological activities, including anticancer activity. The results obtained from this study indicate that molecular modification of stigmasterol functional groups can generate structural analogues with improved anticancer activity. Stigmasterol derivatives have potential as candidates for novel anticancer drugs.
豆甾醇是一种不饱和植物甾醇，属于富含在菝葜属植物中的四环甾醇类。豆甾醇是一种重要的成分，因为它具有令人印象深刻的药理作用，如抗骨关节炎、抗癌、抗糖尿病、抗炎、抗寄生虫、免疫调节、抗真菌、抗氧化、抗菌和神经保护活性。此外，由于存在π 系统和羟基，豆甾醇可以通过取代和加成反应容易地衍生化，允许合成各种豆甾醇衍生物。
从菝葜属植物中分离出的豆甾醇（1）被用作起始原料，通过乙酰化、环氧化、环氧化开环、氧化和二羟基化反应生成八种生物活性衍生物（2-9）。所有化合物的结构均通过光谱技术、NMR、IR、MS 和熔点确定。合成的豆甾醇衍生物通过 Resazurin 测定法筛选对激素受体阳性乳腺癌（MCF-7）、三阴性乳腺癌（HCC70）和非肿瘤性乳腺上皮（MCF-12 A）细胞系的细胞毒性。
成功合成了八种豆甾醇衍生物，分别为：豆甾醇乙酸酯（2）、豆甾-5,22-二烯-3,7-二酮（3）、5,6-环氧豆甾-22-烯-3β-醇（4）、5,6-环氧豆甾-3β,22,23-三醇（5）、豆甾烷-3β,5,6,22,23-五醇（6）、豆甾-5-烯-3,7-二酮-22,23-二醇（7）、豆甾-3,7-二酮-5,6,22,23-醇（8）和豆甾-5-烯-3β,22,23-三醇（9）。这是首次报道豆甾-5-烯-3,7-二酮-22,23-二醇（7）和豆甾-3,7-二酮-5,6,22,23-醇（8）。与未测试的三种细胞系（EC > 250 µM）相比，合成的豆甾醇类似物总体表现出改善的细胞毒性活性。特别是 5,6-环氧豆甾-22-烯-3β-醇（4）和豆甾-5-烯-3β,22,23-三醇（9）对 MCF-7 乳腺癌细胞表现出改善的细胞毒性和选择性（EC 值分别为 21.92 和 22.94 µM），而豆甾烷-3β,5,6,22,23-五醇（6）对 HCC70 细胞系表现出改善的细胞毒性活性（EC：16.82 µM）。
来自菝葜属植物的天然产物及其衍生物表现出广泛的药理活性，包括抗癌活性。本研究结果表明，豆甾醇功能基团的分子修饰可以产生具有改善抗癌活性的结构类似物。豆甾醇衍生物有可能成为新型抗癌药物的候选物。
