Synthesis, Structure, and Cytotoxic Activities of a Novel Lactam of the Diterpenoid Isosteviol
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SYNTHESIS, STRUCTURE, AND CYTOTOXIC ACTIVITIES OF A NOVEL LACTAM OF THE DITERPENOID ISOSTEVIOL
Cong-Jun Liu,1,2* Jing-Jing Li,1 Yu-Tao Min,1 Ling-Li Zhang,1 Bao-Yu Wang,1 and Ya-Hao Wang1
A novel compound lactam of 15β-hydroxymethylisosteviol ethyl ester 3 has been synthesized and structurally characterized by IR, NMR, and HR-MS. Its X-ray crystallographic analysis revealed that the nitrogen is attached to C-13 instead of C-15. The reaction mechanism was discussed, and the title compound was further evaluated against HCT-116, HGC-27, and JEKO-1 cells by the MTT assay. The results demonstrated that compound 3 exhibited better cytotoxic activities than its corresponding precursor isosteviol. Keywords: isosteviol, synthesis, cytotoxic activity. Isosteviol (ent-16-ketobeyeran-19-oic acid, 1), a metabolite of stevioside originally isolated from the natural Stevia rebaudiana Bertoni, is a tetracyclic diterpenoid with the beyerane skeleton [1, 2]. In recent years, isosteviol as well as its derivatives have been shown to exhibit a wide range of biological activities, such as antihyperglycemic [3], antihypertension [4], and antimicrobial [5] activities, as well as anticancer activity [6]. In particular, when some bioactive structural fragments, such as exo-methylene cyclopentanone, amino-alcohol, and so on, were bridged onto the isosteviol skeleton, these hybridized isosteviol derivatives can display promising anticancer activities [7, 8]. The acylamino group is an important structural fragment of many pharmaceutical molecules [9–11]. Introduction of the acylamino group to terpenoid compounds can enhance their existing biological properties or lead to new biological capabilities [12]. However, few reports have focused on the relationship of amide-fused isosteviol structure with anticancer activities. Based on these findings and in continuation of our previous work, a lactam-fused isosteviol derivative was designed and synthesized by a ring-expansion reaction (Scheme 1), and its antitumor activity was also evaluated in order to screen out highly active lead compounds with application values. 17 11 1 A
7
5
O D
9 B
3
18
13
C
NOH
16
a
15
OH COOEt
COOH 19
1
2
O
NH O
CN
+
OH
OH COOEt
+
+
4
CN
OH COOEt
COOEt
COOEt 3
CN
5
6
a. BF3⋅OEt2, toluene, reflux
Scheme 1 1) College of Chemical Engineering and Food Technology, Zhengzhou Institute of Technology, Zhengzhou, 450044, Henan, P. R. China, fax: +86 0371 68229079, e-mail: [email protected]; 2) Postdoctoral Innovation Practice Base, Zhengzhou Institute of Technology, Zhengzhou, 450044, Henan, P. R. China. Published in Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2020, pp. 741–744. Original article submitted September 8, 2019. 0009-3130/20/5605-0865 ©2020 Springer Science+Business Media, LLC
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TABLE 1. Comparison of Rearrangement Products of Compound 2 Under Different Catalysts (refluxed, 15 h) Catalyst–solvent
Yield
BF3·OEt2–toluene
H2SO4–acetone
81% 8% (4–5, 3:1) 7%
33% 54% (4–5, 3:1) 8%
3 4–5 6
TABLE 2. Cytotoxic Activ
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