A Series of New Ligustrazine-Triterpenes Derivatives as  Anti-Tumor Agents: Design, Synthesis, and Biological Evaluation

Xu, Bing; Chu, Fuxiang; Zhang, Yuzhong; Wang, Xiaobo; Li, Qiang; Liu, Wei; Xu, Xin; Xing, Yanyi; Chen, Jing; Wang, Penglong; Lei, Haimin

doi:10.3390/ijms160921035

Cited by 22 publications

(11 citation statements)

References 41 publications

(50 reference statements)

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“…As shown in Scheme 1 , Scheme 2 , Scheme 3 and Scheme 4 , all the designed derivatives were synthesized [ 20 , 24 ]. In Scheme 1 , six kinds of chloromethyl pyrazines were produced by N -chlorosuccinimide (NCS) and benzoyl peroxide (BPO) in carbon tetrachloride (CCl 4 ) under light conditions with nitrogen protection, and the yield ranged from 40–60%.…”

Section: Resultsmentioning

confidence: 99%

“…Pyrazine is an N -heteroaromatic ring, and the incorporation of N -heteroaromatic rings into organic molecules could improve their antitumor activity and aqueous solubility [ 10 , 22 , 23 ]. Our research group proved that the introduction of ligustrazine to betulinic acid, ursolic acid, glycyrrhetinic acid, and oleanolic acid could significantly improve their antitumor effects in vitro [ 24 , 25 ]. Among them ( Figure 1 ), compound 3β-hydroxyolea-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (I), 3β-hydroxyurs-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (II), and 3β-hydroxy-lup-20(29)-ene-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (III) exhibited significant cytotoxicity against a variety of tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Fang

Zhang

Han

et al. 2018

IJMS

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Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He–pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure–activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Fang

Zhang

Han

et al. 2018

IJMS

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“…Synthesis was initiated by oxidation of ligustrazine 1 with hot KMnO 4 solution to afford 3,5,6-trimethylpyrazine-2-carboxylic acid 2. 19 Then, carboxylic acid 2 underwent coupling with p-aminobenzoic acid 3a, p-aminophenylacetic acid 3b, and m-aminobenzoic acid 4 via 1ʹ-carbonyldiimidazole (CDI) to furnish the key intermediates 4a,b and 6, respectively. Then, the target ligustrazinebased HDACIs (7a-c and 8a, b) were obtained, with 45-60% yield, via coupling of key intermediates 4a,b and 6 with hydrazine hydrate or hydroxylamine by the use of CDI (Scheme 1).…”

Section: Results and Discussion Chemistrymentioning

confidence: 99%

“…15,16 Accordingly, ligustrazine has attracted considerable attention as a privileged scaffold in cancer drug discovery. In this context, several studies reported the development of different ligustrazine-based hybrids such as ligustrazine-curcumin hybrids, 17,18 ligustrazine-terpenes hybrids 19 and others. 20,21 The aforementioned findings have inspired and guided us to design and synthesize a new set of HDAC inhibitors (7a-c and 8a,b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

<p>Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety</p>

Al-Sanea

Gotina

Mohamed

et al. 2020

DDDT

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Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates. Methods: This work describes design and synthesis of a new set of HDAC inhibitors (7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition. Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC 50 range: 53.7-205.4 nM) than HDAC1 (IC 50 range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors (7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O). Discussion: Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC 50 values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC 50 = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC 50 = 7.63 µM) against SH-SY5Y cells. Whereas, compound 8a (IC 50 = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC 50 = 4.99 µM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.

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“…Many effective bivalent anti-cancer drugs have been found, such as artemisinin-derivative dimers [10], jesterone dimer [11], indole-3-carbinol dimer [12], bis-daunorubicin [13]. Previous work in this field has designed and synthesized several ligustrazine dimers linked by cyclohexanone and oxime [14], curcumin [15], or triterpenes [16], which had a good cytotoxic effect on human cancer cells. The result showed that the dimerization of ligustrazine could obviously improve the antitumor potency of its monomer.…”

Section: Introductionmentioning

confidence: 99%

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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A Series of New Ligustrazine-Triterpenes Derivatives as Anti-Tumor Agents: Design, Synthesis, and Biological Evaluation

Cited by 22 publications

References 41 publications

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

<p>Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety</p>

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

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