Amino Acid Derivatives of Ligustrazine-Oleanolic Acid as New Cytotoxic Agents

Chu, Fuxiang; Xu, Xin; Li, Guoliang; Gu, Shaohua; Xu, Kuo; Gong, Yan; Xu, Bing; Wang, Mina; Zhang, Huazheng; Zhang, Yuzhong; Wang, Penglong; Lei, Haimin

doi:10.3390/molecules191118215

Cited by 31 publications

(32 citation statements)

References 37 publications

(46 reference statements)

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“…Compounds 3a-g showed strong inhibitory activities against Hep-G2 cells, but a poor inhibitory effect on HSF cells. This result is consistent with the test results of novel ligustrazine-oleanolic acidamino acid derivatives synthesized by Chu et al 31 The R 1 group was 4-(1H-indol-3-yl)butyroxy long-chain-substituted compound (3b, IC 50 8.97±0.13 μM), which had a significantly stronger inhibitory activity against Hep-G2 cells than 2-(1H-indol-3-yl)acetoxy short-chain-substituted compound (3a, IC 50 24.47±1.18 μM). Introducing salicyloyloxy (3d) to C-3 position of 2a led to a significant increase of the selective inhibitory activity with a low IC 50 value of 4.06±0.24 μM on Hep-G2 cells, but for HSF cells, it exhibited a poor inhibitory effect with a high IC 50 value of 79.94±4.42 μM.…”

Section: Results and Discussion Chemistrysupporting

confidence: 93%

“…Gefitinib and doxorubicin were used as positive controls. 40 Considering that the literatures related to this study used both micromolar studies of the cytotoxicity of OA and GA derivatives, 31,32,41,42 so this research used micromolar to study the cytotoxicity of the compounds 1a,b, 2a,b, 3a-n, 5a,b, 6a,b and 7a,b. The antitumor activities were expressed in terms of IC 50 (μM) and are summarized in Table 1.…”

Section: Results and Discussion Chemistrymentioning

confidence: 99%

“…Chu et al reported the first preparation of ligustrazine-oleanolic acid and then the introduction of amino acid fragments to obtain new compounds with high inhibitory activities. 31 Li et al reported that first the preparation of GA esters and then the introduction of 3-(1H-benzo [d] imidazol-2-yl)propanoic acid fragments can greatly improve the anticancer activity, as compared with GA itself. 32 In this research, we use the method of combination to prepare OA and GA esters to increase their lipophilicity and introduce organic acid groups to increase their polarity.…”

Section: Introductionmentioning

confidence: 99%

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Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

Wang¹,

Yang²,

Huai³

et al. 2018

DDDT

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BackgroundThe structural modification of natural products with the aim to improve the anticancer activity is a popular current research direction. The pentacyclic triterpenoid compounds oleanolic acid (OA) and glycyrrhetinic acid (GA) are distributed widely in nature.MethodsIn this study, various oleanolic acids and glycyrrhetinic acids were designed and synthesized by using the combination principle. The in vitro anticancer activities of new OA and GA derivatives were tested by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method with SGC-7901 (gastric cancer), MCF-7 (breast cancer), Eca-109 (esophageal cancer), HeLa (cervical cancer), Hep-G2 (hepatoma cancer) and HSF (normal human skin fibroblast) cells.Results and conclusionThe screening results showed that the compound 3m presented the highest inhibitory activities against SGC-7901, MCF-7 and Eca-109 cell lines with IC50 values of 7.57±0.64 μM, 5.51±0.41 μM and 5.03±0.56 μM, respectively. In addition, this compound also showed effective inhibition of Hep-G2 cells with an IC50 value of 4.11±0.73 μM. Moreover, compound 5b showed the strongest inhibitory activity against Hep-G2 cells with an IC50 value of 3.74±0.18 μM and compound 3l showed strong selective inhibition of the HeLa cells with the lowest IC50 value of 4.32±0.89 μM. A series of pharmacology experiments indicated that compound 5b could induce Hep-G2 cells autophagy and apoptosis. These compounds will expand the structural diversity of anti-cancer targets and confirm the prospects for further research.

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Section: Results and Discussion Chemistrysupporting

confidence: 93%

Section: Results and Discussion Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

Wang¹,

Yang²,

Huai³

et al. 2018

DDDT

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“…The results revealed that 8e could induce FaDu cells' apoptosis in a dose-dependent manner. This was consistent with other reports showing TMP and its derivatives could induce apoptosis of cancer cells [22][23][24].…”

Section: Apoptosis Analysis By Annexin V-fitc/pi Stainingsupporting

confidence: 94%

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

Wang

Hong

et al. 2019

Molecules

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Bivalent and polyvalent inhibitors can be used as antitumor agents. In this experiment, eight ligustrazine dimers and seven ligustrazine tetramers linked by alkane diamine with different lengths of carbon chain lengths were synthesized. After screening their antiproliferation activities against five cancer cell lines, most ligustrazine derivatives showed better cytotoxicity than the ligustrazine monomer. In particular, ligustrazine dimer 8e linked with decane-1,10-diamine exhibited the highest cytotoxicity in FaDu cells with an IC50 (50% inhibiting concentration) value of 1.36 nM. Further mechanism studies suggested that 8e could induce apoptosis of FaDu cells through the depolarization of mitochondrial membrane potential and S-phase cell cycle arrest. Inspired by these results, twenty-seven additional small molecule heterocyclic dimers linked with decane-1,10-diamine and nine cinnamic acid dimers bearing ether chain were synthesized and screened. Most monocyclic and bicyclic aromatic systems showed highly selective anti-proliferation activity to FaDu cells and low toxicity to normal MCF 10A cells. The structure-activity relationship revealed that the two terminal amide bonds and the alkyl linker with a chain length of 8–12 carbon were two important factors to maintain its antitumor activity. In addition, the ADMET calculation predicted that most of the potent compounds had good oral bioavailability.

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“…[23] Likewise, it has revealed that the incorporation of different amino acids, especially positively charged amino acids, to natural products might improve the water solubility and bioavailability as well as increase their biological activities. [25,26] In addition, polyarginine peptides, which are rich in cationic charges, have high affinities for bacterial membranes and play an important role as they selectively interact with the membrane. [27] Thus, the fusion of polyarginine peptides with pentacyclic triterpenes would possibly change the physicochemical properties and enhance the antimicrobial activities of bioactive triterpenes and polyarginine peptides.…”

Section: Introductionmentioning

confidence: 99%

Triterpene sapogenin–polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains

Na¹,

Li²,

Zou³

et al. 2016

Bioorganic & Medicinal Chemistry

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Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charged cell membranes and possess moderate antibacterial activities. In this study, we designed and synthesized a series of sapogenin-polyarginine conjugates in which the triterpene sapogenin moiety was covalently appended to the positively charged polyarginine via click chemistry. A clear synergistic effect was found, and the conjugates exhibited potent and selective antibacterial activity against Gram-positive strains. Among them, BAc-R3 was the most promising compound, which was also proven to be nontoxic toward mammalian cells as well as stable in plasma. The mechanism of BAc-R3 primarily involves an interaction with the bacterial membrane, similar to that of antimicrobial peptides (AMPs). This scaffold design opens an avenue for the further development of novel antibiotics comprised of the combination of a peptide and a natural product.

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Amino Acid Derivatives of Ligustrazine-Oleanolic Acid as New Cytotoxic Agents

Cited by 31 publications

References 37 publications

Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

Triterpene sapogenin–polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains

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