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DOI: 10.1055/a-2239-6717
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Carbohydrate Chemistry in China

Chemical Synthesis and Antitumor Evaluation of Chikusetsusaponin IVa Butyl Ester and Its Analogues

Jibin Zheng
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Yanxiao Wang
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Yiyue Zhang
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Jingjing Rong
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Dongjuan He
b   The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 100 Minjiang Road, Quzhou, Zhejiang 324000, P. R. of China
c   Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Hongshan Road, Nanjing 210028, P. R. of China
,
Xiaotong Wang
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Liangliang Zhang
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
,
Jianguang Xu
b   The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 100 Minjiang Road, Quzhou, Zhejiang 324000, P. R. of China
c   Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Hongshan Road, Nanjing 210028, P. R. of China
,
Peng Cao∗
b   The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, 100 Minjiang Road, Quzhou, Zhejiang 324000, P. R. of China
c   Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Hongshan Road, Nanjing 210028, P. R. of China
,
You Yang  ∗
a   Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
› Author AffiliationsFinancial support from the National Natural Science Foundation of China (22071054, 21871081, 82125037), the National Key R&D Program of China (2023YFC2308200), the Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission), and the Jiangsu Provincial Medical Innovation Center (CXZX202225) is gratefully acknowledged.
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Abstract

Chikusetsusaponin IVa butyl ester (CS-IVa-Be) is a triterpene saponin that acts as a novel IL6R antagonist for inducing breast cancer cell apoptosis. However, the structure–activity relationship for this class of saponins remains unclear. Here, we report a gram-scale synthesis of CS-IVa-Be and the efficient preparation of eight of its analogues. CS-IVa-Be was demonstrated to have significant antitumor activities against MDA-MB-231, HepG2, and A549 cells. When one of the sugar residues at either the 3-OH or 28-COOH position of CS-IVa-Be was cleaved, or the length of the alkyl chain on the d-glucuronic acid residue of CS-IVa-Be was changed, these analogues showed varied inhibitory activities against the cancer cell lines. Notably, the carboxylic acid form of CS-IVa-Be exhibited a stronger antitumor activity against MDA-MB-231 cells. Furthermore, the carboxylic acid form of CS-IVa-Be inhibited MDA-MB-231 cell proliferation in a dose-dependent manner by arresting the cell cycle at the G2/M phase.

Key words

glycosides - glycosylation - carbohydrates - natural products - medicinal chemistry

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2239-6717.
  • Supporting Information


Publication History

Received: 01 December 2023

Accepted after revision: 05 January 2024

Accepted Manuscript online:
05 January 2024

Article published online:
15 February 2024

© 2024. Thieme. All rights reserved

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  • 17 Chikusetsusaponin IVa Alkyl Esters; General Procedure NaOMe (10 equiv) was added to a solution of carboxylic acid 13 (1 equiv) in 2:1 CH2Cl2–MeOH at r.t. under argon, and the mixture was stirred at r.t. for 24 h until the starting material was completely converted (TLC). The mixture was then neutralized with Amberlite IR120 H+ resin and filtered. The filtrate was concentrated in vacuo and purified by C18 column chromatography. The residue was dissolved in anhyd DMF and KHCO3 (0.9–2.3 equiv), and the appropriate alkyl iodide (2 equiv) was added. The mixture was stirred overnight at r.t. until the starting material was completely consumed (TLC). The mixture was then neutralized with 1 M aq HCl, and concentrated in vacuo. The residue was purified by column chromatography (silica gel). 1 Yellow foamy solid; yield: 1.59 g (79%, two steps); [α]D 25 +2.7 (c = 0.83, MeOH). 1H NMR (400 MHz, pyridine-d5 ): δ = 6.32 (d, J = 8.0 Hz, 1 H, H-1 of Glc), 5.42 (br s, 1 H), 5.00 (d, J = 7.6 Hz, 1 H, H-1 of GlcA), 4.62 (d-like, J = 9.6 Hz, 1 H), 4.54–4.46 (m, 2 H), 4.43–4.20 (m, 7 H), 4.13–4.03 (m, 2 H), 3.35 (dd, J = 4.4, 11.6 Hz, 1 H), 3.18 (dd, J = 4.0, 14.0 Hz, 1 H), 1.28 (s, 3 H), 1.27 (s, 3 H), 1.08 (s, 3 H), 0.96 (s, 3 H), 0.91 (s, 3 H), 0.87 (s, 3 H), 0.83 (s, 3 H), 0.76 (t, J = 7.2 Hz, 3 H). 13C NMR (150 MHz, pyridine-d5 ): δ = 176.8, 170.4, 144.2, 122.8, 107.2, 95.7, 89.2, 79.2, 78.7, 77.9, 77.2, 75.3, 74.0, 73.0, 71.0, 65.0, 62.1, 55.7, 48.0, 47.0, 46.1, 42.1, 41.7, 39.8, 39.4, 38.7, 36.9, 33.9, 33.1, 32.5, 30.8, 30.7, 28.1, 28.0, 26.6, 26.1, 23.8, 23.6, 23.3, 19.2, 18.4, 17.4, 16.9, 15.5, 13.7. HRMS (ESI): m/z [M + Na]+ calcd for C46H74NaO14 873.4976; found: 873.4974 5 White solid; yield: 4.4 mg (79%); [α]D 25 +5.0 (c = 0.03, MeOH). 1H NMR (400 MHz, CD3OD): δ = 5.38 (d, J = 8.0 Hz, 1 H), 5.25 (br s, 1 H), 4.33 (d, J = 8.0 Hz, 1 H), 3.82 (d, J = 11.6 Hz, 1 H), 3.68 (dd, J = 3.2, 11.6 Hz, 1 H), 3.54 (d, J = 9.6 Hz, 1 H), 3.46–3.37 (m, 3 H), 3.36–3.34 (m, 3 H), 3.26–3.17 (m, 2 H), 2.85 (dd, J = 4.0, 14.0 Hz, 1 H), 1.15 (s, 3 H), 1.05 (s, 3 H), 0.95 (s, 3 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.85 (s, 3 H), 0.80 (s, 3 H). 13C NMR (150 MHz, CD3OD): δ = 178.1, 177.0, 144.8, 123.9, 106.7, 95.7, 90.7, 78.7, 78.3, 78.0, 76.6, 75.6, 73.9, 73.8, 71.1, 62.4, 57.0, 49.6, 48.0, 47.2, 42.9, 42.6, 40.7, 40.2, 39.9, 37.9, 34.9, 34.0, 33.5, 33.2, 31.5, 28.9, 28.5, 26.9, 26.3, 24.6, 24.0, 23.9, 19.3, 17.7, 17.0, 16.0. HRMS (ESI): m/z [M + Na]+ calcd for C42H66NaO14: 817.4350; found: 817.4352. 7 White solid; yield: 9.6 mg (90%). 1H NMR (600 MHz, CD3OD): δ = 5.38 (d, J = 7.8 Hz, 1 H), 5.25 (t, J = 3.6 Hz, 1 H), 4.38 (d, J = 7.8 Hz, 1 H), 4.25–4.21 (m, 2 H), 3.83–3.79 (m, 2 H), 3.68 (dd, J = 4.2, 12.0 Hz, 1 H), 3.52 (t, J = 9.6 Hz, 1 H), 3.41 (t, J = 9.0 Hz, 1 H), 3.37–3.33 (m, 4 H), 3.23 (dd, J = 7.8, 9.0 Hz, 1 H), 3.15 (dd, J = 4.2, 12.0 Hz, 1 H), 2.85 (dd, J = 4.2, 13.8 Hz, 1 H), 1.16 (s, 3 H), 1.04 (s, 3 H), 0.95 (s, 3 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.85 (s, 3 H), 0.80 (s, 3 H). HRMS (ESI): m/z [M + Na]+ calcd for C44H70NaO14: 845.4663; found: 845.4662. 8 White solid; yield: 11.3 mg (99%); [α]D 25 +4.0 (c = 0.03, MeOH). 1H NMR (600 MHz, CD3OD): δ = 5.38 (d, J = 8.4 Hz, 1 H), 5.25 (t, J = 3.0 Hz, 1 H), 4.38 (d, J = 7.8 Hz, 1 H), 4.23–4.15 (m, 2 H), 3.82–3.79 (m, 2 H), 3.68 (dd, J = 4.2, 12.0 Hz, 1 H), 3.54 (t, J = 9.6 Hz, 1 H), 3.41 (t, J = 9.0 Hz, 1 H), 3.37–3.33 (m, 4 H), 3.24 (t, J = 9.0 Hz, 1 H), 3.15 (dd, J = 4.2, 12.0 Hz, 1 H), 2.85 (dd, J = 4.2, 13.8 Hz, 1 H), 1.16 (s, 3 H), 1.04 (s, 3 H), 0.95 (s, 3 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.85 (s, 3 H), 0.80 (s, 3 H). 13C NMR (150 MHz, CD3OD): δ = 178.0, 170.9, 144.9, 123.8, 107.1, 95.7, 91.0, 78.7, 78.3, 77.5, 76.7, 75.3, 73.9, 73.0, 71.1, 66.4, 62.4, 57.0, 49.6, 48.0, 47.2, 42.9, 42.6, 40.7, 40.2, 39.9, 37.9, 34.9, 33.9, 33.5, 33.1, 32.7, 31.5, 29.7, 28.9, 28.4, 27.1, 26.8, 26.3, 24.6, 24.0, 23.9, 23.7, 19.3, 17.7, 16.9, 16.0, 14.5. HRMS (ESI): m/z [M + Na]+ calcd for C48H78NaO14: 901.5289; found: 901.5286.