Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Ohori, Hisatsugu; Yamakoshi, Hiroyuki; Tomizawa, Masaki; Shibuya, Masabumi; Kakudo, Yuichi; Takahashi, Akihiro; Takahashi, S.; Kato, Satoshi; Suzuki, Takao; Ishioka, Chikashi; Iwabuchi, Yoshiharu; Shibata, Hiroyuki

doi:10.1158/1535-7163.mct-06-0174

Cited by 221 publications

(175 citation statements)

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“…From these experiments, we found that GO-Y016, GO-Y030, and GO-Y031 exhibited in vitro cancer cell growth inhibition with a GI 50 value of 0.3 μM. 5 Moreover, GO-Y030 exhibited in vivo chemopreventive activity in the familial adenomatous polyposis (FAP) mouse without apparent toxicity. 6 However, its mode of action has remained elusive.…”

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confidence: 96%

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

Yamakoshi

Kanoh

Kudo

et al. 2010

ACS Med. Chem. Lett.

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Bis(arylmethylidene)acetone derivatives are an important class of curcumin analogues that exhibit various biological and pharmacological activities. We herein report that GO-Y086, a biotinylated bis(arylmethylidene)acetone, inhibits cancer cell growth. We also show that GO-Y086 specifically interacts with the nuclear protein KSRP/FUBP2 by covalent modification. GO-Y086 markedly suppresses the expression of the c-Myc protein, which plays an important role in cellular proliferation and whose expression is regulated by KSRP/FUBP2.

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confidence: 96%

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

Yamakoshi

Kanoh

Kudo

et al. 2010

ACS Med. Chem. Lett.

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“…23 Recently, synthetic modifications of curcumin have been studied intensively in order to develop a molecule with enhanced properties and stability. [23][24][25][26] In the present study, a series of curcumin analogues with more stable structures were synthesized and tested for anti-inflammatory activity in vitro. Several analogues showed an enhanced ability to inhibit lipopolysaccharide (LPS)-induced TNF-α and IL-6 in macrophages.…”

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confidence: 99%

Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin

Liang

Chen

et al. 2008

Bioorganic & Medicinal Chemistry Letters

129

113

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Curcumin has been extensively studied for its anti-inflammatory activities. However, its potential beneficial effects on various disease preventions and treatments are limited by its unstable structure. The β-diketone moiety renders curcumin to be rapidly metabolized by aldoketo reductase in liver. In the present study, a series of curcumin analogues with more stable chemical structures were synthesized and several compounds showed an enhanced ability to inhibit lipopolysaccharide (LPS)-induced TNF-α and IL-6 synthesis in macrophages.Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, Fig. 1] is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. Tumeric has been widely used for centuries as a dietary spice and pigment. 1 In addition to its unique flavor and color, tumeric has been extensively used in traditional medicine in China and India, particularly as an anti-inflammatory agent. 2 During the last two decades, numerous studies have shown that curcumin has a variety of biological and pharmacological activities such as anti -carcinogen, immuno-modulation, anti-oxidant, antiangiogenesis, and chemo-prevention. 3-9 Recent studies have demonstrated that inflammation is implicated in the pathogenesis of various diseases including cancer, atherosclerosis, diabetes, fatty liver, rheumatoid arthritis, and inflammatory bowel disease. 10-13 Anti-inflammation is the major focus of current drug development. 14 Cytokines are local mediators produced by lymphocytes and macrophages as well as by epithelial and mesenchymal cells. 15 It has been demonstrated that cytokines are involved in a variety of biological processes and play a central role in the development of inflammation and immunity. TNF-α is a multifunctional cytokine produced primarily by activated monocytes/macrophages and plays a critical role in the initiation and continuation of inflammation and immunity. 16 It is well-known that TNF-α is a key proinflammatory cytokine in the pathogenesis of various inflammatory diseases and cancer. 13, 17 In addition to directly *Corresponding authors: Huiping Zhou: 1217 East Marshall Street, MSB#533, Richmond, VA 23298, USA. E-mail: hzhou@vcu.edu; Tel:804-828-6817; Fax:804-828-0676., Xiaokun Li: College of Pharmacy, Wenzhou Medical College., E-mail: xiaokunli@163.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In order to identify the crucial structural motifs leading to anti-inflammatory activity and gain insight into future directions for designing new analogues with better activity, thre...

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“…The results of a Phase II www.chinaphar.com Peng YM et al Acta Pharmacologica Sinica npg trial indicated that this compound is safe to administer but has a low bioavailability owing to its extremely limited water solubility [24] . Therefore we examined the water solubility of P1 and found it to be 14 μmol/L, whereas that of curcumin is 1.5 μmol/L.…”

Section: Discussionmentioning

confidence: 99%

“…Curcumin inhibits the proliferation of many cancer cells in vitro and in vivo [23] . A phase II trial indicated that chronic oral administration of curcumin had limited clinical benefits due to its low bioavailability [24] . We report here the identification of P1, a tropinone curcumin analog and a novel NF-κB inhibitor and apoptosis inducer.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms

et al. 2013

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Aim: Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-κB pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms. Methods: HEK293/NF-κB cells, stably transfected with an NF-κB-responsive luciferase reporter plasmid, were generated for highthroughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H 2 -DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay. Results: P1, a tropinone curcumin, was found in HTS targeting the NF-κB pathway. Its IC 50 value in inhibition of TNF-α-induced NF-κB activation was 0.8 μmol/L, whereas its IC 50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 μmol/L, respectively, which was 20-to 30-fold more potent than curcumin. The inhibition of P1 on the NF-κB pathway was further addressed in HeLa cells. The compound up to 10 µmol/L did not affect the binding of NF-κB to DNA, but markedly inhibited NF-κB nuclear translocation, IκB degradation and IκB kinase phosphorylation. The compound (1 and 3 µmol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 µmol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-α-induced apoptosis. Conclusion: P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-κB pathway.

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Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Cited by 221 publications

References 25 publications

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin

Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-κB signaling pathway with distinct mechanisms

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