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 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 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 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI50) against the most sensitive cell lines at submicromolar concentrations (0.20-0.94 μM), and their cytotoxic activity (LC50) was also high (1-6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI50 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 3 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 GI50 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.

中文翻译：

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a-Azepano-和3-Amino-3,4-SeCo-Triterpenoids的细胞毒性潜能。

半合成的三萜类化合物，具有氨基取代的七元A环（氮杂环庚烷环），可以通过贝克曼型重排，然后还原内酰胺片段，由三萜肟合成，被认为是新型的有前途的药物，具有抗-微生物，α-葡萄糖苷酶和丁酰胆碱酯酶的抑制活性。在这项研究中，为开发新的抗肿瘤候选药物，评估了一系列的甜菜碱酸，齐墩果酸，熊果酸和甘草次酸的A-环氮杂环丁烷和3-氨基-3,4-seco衍生物的抗细胞毒活性。通过比色磺基罗丹明测定，可检测出五种人类癌细胞系和非恶性小鼠成纤维细胞。Azepanoallobetulinic酰胺衍生物11是该系列中最具细胞毒性的化合物，但在不同的人类肿瘤细胞系之间显示出很小的选择性。流式细胞术实验表明化合物11主要通过凋亡（44.3％）和晚期凋亡（21.4％）起作用。这些化合物在美国国家癌症研究所进一步针对60个癌细胞系进行了筛选。发现化合物3、4、7、8、9、11、15、16、19和20在亚微摩尔浓度（0.20-0.94μM）下对最敏感的细胞系表现出生长抑制（GI50）及其细胞毒性活性（LC50）也很高（1-6μM）。衍生物3、8、11、15和16在GI50水平上对K-562，CCRF-CEM，HL-60（TB）和RPMI-8226（白血病），HT29（结肠）表现出一定的选择性，从5.16至9.56癌症），和OVCAR-4（卵巢癌）细胞系。TGI水平上的氮杂四氢呋喃二醇3的选择性指数范围从5.93（CNS癌细胞系SF-539，SNB-19和SNB-75）到HCT-116（结肠癌）的14.89，SI 9.56在GI50水平对白血病细胞系K -562。本研究强调了三萜核中A-氮杂环庚烷环对于开发新型抗肿瘤药的重要性，因此，提高选择性的未来目标将在于对氮杂环丙烷-三萜酸的羧基进行修饰。 。