Discovery of New Monocarbonyl Ligustrazine–Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

Ai, Yong; Zhu, Bin; Ren, Chao; Kang, Fenghua; Li, Jinlong; Huang, Zhangjian; Lai, Yisheng; Peng, Sixun; Ding, Ke; Tian, Jide; Zhang, Yihua

doi:10.1021/acs.jmedchem.5b01203

Cited by 61 publications

(40 citation statements)

References 80 publications

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“…All of the five compounds exerted potent TrxR inhibitory activity (IC 50 = 1.22–4.73 μM). Most surprisingly, compound 211 exhibited the highest TrxR inhibitory activity, which was ∼32‐fold more potent than positive drug curcumin . The interaction of dimethoxycurcumin ( 216 , Figure ) with TrxR was explored by Sandur and co‐workers.…”

Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

133

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

133

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“…The complex chemistry of curcumin allows it to inhibit multiple oncogenic processes, including those associated with the JAK2/STAT3 pathway or the induction of ROS production293031. To improve the potency of curcumin as a cancer therapeutic agent, many synthetic curcumin analogues have been developed as new JAK2/STAT3 inhibitors, including FLLL31, FLLL32 and FLL62171819.…”

mentioning

confidence: 99%

Discovery of monocarbonyl curcumin-BTP hybrids as STAT3 inhibitors for drug-sensitive and drug-resistant breast cancer therapy

Zhang

Guo

et al. 2017

Sci Rep

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Signal transducer and activator of transcription 3 (STAT3) is a well-known antitumor target. Exogenous ROS insult can lead to selective cytotoxicity against cancer cells. A combination of STAT3 inhibition and “oxidation therapy” may be a new strategy to address the multidrug-resistance issue due to their important roles in the survival and drug resistance of cancer cells. Here, a series of novel curcumin-BTP hybrids were designed and evaluated as STAT3 inhibitors with ROS production activity. Compound 6b exerted the best antitumor activity and selectivity for MCF-7 and MCF-7/DOX cells (IC50 = 0.52 μM and 0.40 μM, respectively), while its IC50 value for MCF-10A breast epithelial cells was 7.72 μM. Furthermore, compound 6b suppressed STAT3 phosphorylation, nuclear translocation and DNA-binding activity and the expression of STAT3 specific oncogenes. Increases in the level of IL-6-induced p-STAT3 were also inhibited by 6b without influencing IFN-γ-induced p-STAT1 expression. Additionally, 6b effectively promoted intracellular ROS accumulation, induced cancer cell apoptosis and cell cycle arrest, abolished the colony formation ability of breast cancer cells, and inhibited P-gp expression in MCF-7/DOX cells. Finally, 6b suppressed the growth of implanted human breast cancer in vivo. Our findings highlight that 6b may be a promising therapeutic agent for drug-sensitive and drug-resistant breast cancers.

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“…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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Discovery of New Monocarbonyl Ligustrazine–Curcumin Hybrids for Intervention of Drug-Sensitive and Drug-Resistant Lung Cancer

Cited by 61 publications

References 80 publications

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Discovery of monocarbonyl curcumin-BTP hybrids as STAT3 inhibitors for drug-sensitive and drug-resistant breast cancer therapy

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

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