Ceramicines M–P from Chisocheton ceramicus: isolation and structure–activity relationship study

Abstract

Ceramicines are a series of limonoids which were isolated from the bark of Malaysian Chisocheton ceramicus (Meliaceae) and show various biological activities. Ceramicine B, in particular, has been reported to show a strong lipid droplet accumulation (LDA) inhibitory activity on a mouse pre-adipocyte cell line (MC3T3-G2/PA6). With the purpose of discovering compounds with stronger activity than ceramicine B, we further investigated the constituents of C. ceramicus. As a result, from the bark of C. ceramicus four new ceramicines (ceramicines M-P, 1-4) were isolated, and their structures were determined on the basis of NMR and mass spectroscopic analyses in combination with NMR chemical shift calculations. LDA inhibitory activity of 1-4 was evaluated. Compounds 1-3 showed LDA inhibitory activity, and 3 showed better selectivity than ceramicine B while showing activity at the same order of magnitude as ceramicine B. Since 3, which possess a carbonyl group at C-7, showed better selectivity than 5, which possess a 7α-OH group, while showing activity at the same order of magnitude as 5, we also investigated the effect of the substituent at C-7 by synthesizing several derivatives and evaluating their LDA inhibitory activity. Accordingly, we confirmed the importance of the presence of a 7α-OH group to the LDA inhibitory activity.

Computationally-assisted discovery and structure elucidation of natural products

“…DFT-calculated NMR has been used to determine the relative configuration of various natural products, with recent reports on halioxepines A–C isolated from marine sponges of the genus Haliclona ( 10–12 , Fig. 5) [59], xylomolones A–B isolated from Xylocarpus moluccensis Haliclona [60], bisleuconothine B isolated from Leuconotis griffithii Haliclona [61], ceramicine N isolated from Chisocheton ceramicus [62], and walsogyne B isolated from Walsura chrysogyne [63]. It interesting that even in difficult cases such as 10–12 , where two stereoclusters are separated by two methylenes, DFT NMR calculations can accurately predict the relative configurations of the product.

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Walsogynes H–O from Walsura chrysogyne

“…The plants of this genus have been reported to produce limonoids, dammarane, tirucallane and apotirucallane triterpenoids [2][3][4][5][6][7]. In our search for new bioactive compounds [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], we have reported the isolation of new limonoids and triterpenoids from plants of this genus [3,4,19], and alkaloids showing antimalarial activity [22,26,27]. Continuation of the bioassay-guided investigation on the extract of W. chrysogyne bark led to the isolation of eight new limonoids, walsogynes H-O (1)(2)(3)(4)(5)(6)(7)(8) showing antimalarial activity (Fig.…”

Four Flavan-3-ol Compounds From The Stembark of Chisocheton balansae C.DC. (MELIACEAE)

“…Chisocheton is one of the genera of the Meliaceae family, which has 53 species mainly distributed in tropical and subtropical regions such as southern China, Thailand, Malaysia, Vietnam, Indonesia and northern Australia (Shilpi et al, 2016;Zhang, He, Wu, Chen, & Yue, 2012). Studies on the investigation of chemical constituents from Chisocheton plant have been undertaken extensively since 1979 leading to the isolation of various types of compounds, such as limonoids (Awang et al, 2007;Chong et al, 2019;Najmuldeen et al, 2012;Nugroho et al, 2017;Nurlelasari et al, 2017;Supriatno et al, 2018), apotirucallane-type triterpenoids (Xie, Yang, Zhang, & Yue, 2009;Yadav, Kataky, & Mathur, 1999;Yang, Wang, Wang, Kong, & Luo, 2012;Zhang et al, 2012), dammarane-type triterpenoids (Chan, Mohamad, Ooi, Imiyabir, & Chung, 2012;Katja, Harneti, Mayanti, Farabi, & Supratman, 2017;Phongmaykin, Kumamoto, Ishikawa, Suttisri, & Saifah, 2008), lanostane-type triterpenoids (Katja et al, 2016), tirucallane-type triterpenoids (Katja et al, 2017;M. H. Yang, Wang, Luo, Wang, & Kong, 2011), steroids (Huang, Jian, Li, Kong, & Yang, 2016;Najmuldeen et al, 2011), alkaloids (Tzouros et al, 2004), coumarins (Nurlelasari et al, 2014;Phongmaykin et al, 2008) and sesquiterpenoids (Phongmaykin et al, 2008).…”