Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russia.
Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.
Int J Mol Sci. 2021 Feb 8;22(4):1714. doi: 10.3390/ijms22041714.
Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds , , , , , , , , , and showed growth inhibitory (GI) against the most sensitive cell lines at submicromolar concentrations (0.20-0.94 μM), and their cytotoxic activity (LC) was also high (1-6 μM). Derivatives , , , , and demonstrated a certain selectivity profile at GI level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group.
半合成三萜类化合物，具有取代的七元 A 环（氮杂环庚烷环），可通过肟通过 Beckmann 型重排转化为内酯片段，然后还原得到，被认为是具有抗微生物，α-葡萄糖苷酶和丁酰胆碱酯酶抑制活性的新型有前途的药物。在这项研究中，为了开发新的抗肿瘤候选药物，通过比色磺酰罗丹明测定法评估了一系列桦木醇、齐墩果酸、熊果酸和甘草次酸的 A 环氮杂庚烷和 3-氨基-3,4-脱碳衍生物对五种人癌细胞系和非恶性小鼠成纤维细胞的细胞毒性活性。氮杂环庚烷全贝壳杉酸酰胺衍生物 是该系列中最具细胞毒性的化合物，但对不同人肿瘤细胞系之间的选择性很小。流式细胞术实验表明，化合物 主要通过细胞凋亡（44.3％）和晚期细胞凋亡（21.4％）起作用。进一步在国立癌症研究所对 60 种癌细胞系进行了筛选。发现化合物 ， ， ， ， ， ， ， 和 以亚微摩尔浓度（0.20-0.94 μM）对最敏感的细胞系显示出生长抑制（GI）作用，其细胞毒性（LC）也很高（1-6 μM）。衍生物 ， ， ， ， 和 在 GI 水平上对 K-562，CCRF-CEM，HL-60（TB）和 RPMI-8226（白血病），HT29（结肠癌）和 OVCAR-4（卵巢癌）细胞系具有一定的选择性谱，范围从 5.16 到 9.56。氮杂庚烷赤醇 的 TGI 水平的选择性指数范围为 5.93（中枢神经系统癌症细胞系 SF-539、SNB-19 和 SNB-75）至 14.89 用于 HCT-116（结肠癌），SI 为 9.56 用于白血病细胞系 K-562。本研究强调了三萜核心中 A-氮杂庚烷环对开发新型抗肿瘤药物的重要性，因此，增加选择性谱的未来目标将在于对氮杂庚烷三萜酸的羧基进行修饰。
