- Design, synthesis and biological evaluation of novel chalcone-like compounds as potent and reversible pancreatic lipase inhibitors
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Pancreatic lipase (PL), a crucial enzyme responsible for hydrolysis of dietary lipids, has been validated as a key therapeutic target to prevent and treat obesity-associated metabolic disorders. Herein, we report the design, synthesis and biological evaluation of a series of chalcone-like compounds as potent and reversible PL inhibitors. Following two rounds of structural modifications at both A and B rings of a chalcone-like skeleton, structure-PL inhibition relationships of the chalcone-like compounds were studied, while the key substituents that would be beneficial for PL inhibition were revealed. Among all tested chalcone-like compounds, compound B13 (a novel chalcone-like compound bearing two long carbon chains) displayed the most potent PL inhibition activity, with an IC50 value of 0.33 μM. Inhibition kinetic analyses demonstrated that B13 could potently inhibit PL-mediated 4-MUO hydrolysis in a mixed inhibition manner, with the Ki value of 0.12 μM. Molecular docking simulations suggested that B13 could tightly bind on PL at both the catalytic site and a non-catalytic site that was located on the surface of PL, which was consistent with the mixed inhibition mode of this agent. In addition, B13 displayed excellent stability in artificial gastrointestinal fluids and good metabolic stability in human liver preparations. Collectively, our findings suggested that chalcone-like compounds were good choices for design and development of orally administrated PL inhibitors, while B13 could be served as a promising lead compound to develop novel anti-obesity agents via targeting on PL.
- Huo, Peng-Chao,Hu, Qing,Shu, Sheng,Zhou, Qi-Hang,He, Rong-Jing,Hou, Jie,Guan, Xiao-Qing,Tu, Dong-Zhu,Hou, Xu-Dong,Liu, Peng,Zhang, Nan,Liu, Zhi-Guo,Ge, Guang-Bo
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Read Online
- Design, synthesis and biological evaluation of indanone–chalcone hybrids as potent and selective hCES2A inhibitors
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Human carboxylesterase 2 (hCES2A), one of the major serine hydrolases distributed in the small intestine, plays a crucial role in hydrolysis of ester-bearing drugs. Accumulating evidence has indicated that hCES2A inhibitor therapy can modulate the pharmacokinetic and toxicological profiles of some important hCES2A-substrate drugs, such as the anticancer agent CPT-11. Herein, a series of indanone–chalcone hybrids are designed and synthesized to find potent and highly selective hCES2A inhibitors. Inhibition assays demonstrated that most indanone–chalcone hybrids displayed strong to moderate hCES2A inhibition activities. Structure-hCES2A inhibition activity relationship studies showed that introduction of a hydroxyl at the C4’ site and introduction of an N-alkyl group at the C6 site were beneficial for hCES2A inhibition. Particularly, B7 (an N-alkylated 1-indanone–chalcone hybrid) exhibited the most potent inhibition on hCES2A and excellent specificity (this agent could not inhibit other human esterases including hCES1A and butyrylcholinesterase). Inhibition kinetic analyses demonstrated that B7 potently inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a calculated Ki value of 0.068 μM. Furthermore, B7 was capable of inhibiting intracellular hCES2A in living cells and displayed good metabolic stability. Collectively, our findings show that indanone–chalcone hybrids are good choices for the development of hCES2A inhibitors, while B7 is a promising candidate for the development of novel anti-diarrhea agents to ameliorate irinotecan-induced intestinal toxicity.
- Huo, Peng-Chao,Guan, Xiao-Qing,Liu, Peng,Song, Yun-Qing,Sun, Meng-Ru,He, Rong-Jing,Zou, Li-Wei,Xue, Li-Juan,Shi, Jin-Hui,Zhang, Nan,Liu, Zhi-Guo,Ge, Guang-Bo
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Read Online
- Design, synthesis, and structure-activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury
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Purpose: The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Results: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. Conclusion: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.
- Xiao, Siyang,Zhang, Wenxin,Chen, Hongjin,Fang, Bo,Qiu, Yinda,Chen, Xianxin,Chen, Lingfeng,Shu, Sheng,Zhang, Yali,Zhao, Yunjie,Liu, Zhiguo,Liang, Guang
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Read Online
- Curcumin analog, WZ37, promotes G2/M arrest and apoptosis of HNSCC cells through Akt/mTOR inhibition
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Head and neck squamous cell carcinoma (HNSCC) is a leading form of malignancy arising from the head and neck region. Existing conventional therapies are toxic and induce resistance to advanced HNSCC, therefore, new highly efficient therapeutic agents are urgently needed. The present study investigated the anti-cancer efficacy of WZ37, a curcumin analog, in HNSCC cell lines, and defined the mechanism of this activity. Results indicated that WZ37 inhibited proliferation of several HNSCC cell types by G2/M cycle arrest, promoted expression of a pro-apoptotic protein profile, and induced ROS-dependent mitochondrial injury and ER stress. Pre-treatment with NAC, an ROS scavenger, lowered the anti-cancer activity of WZ37 in HEP-2 cells. Long-term treatment of WZ37 (24 h) decreased Akt/mTOR phosphorylation which was accompanied by increased expression of BAD and PTEN. Moreover, co-treatment of WZ37 with MK-2206 (Akt inhibitor) promoted cancer cell apoptosis. Our findings indicated that the anti-cancer potential of WZ37 was attributed to ROS-dependent cell cycle arrest, mitochondrial injury, and ER stress, leading to apoptosis. The basis of the HNSCC cell apoptosis was through a mechanism of inhibition of the oxidant-sensitive Akt/mTOR pathway. We conclude that WZ37 can be a promising anti-cancer agent for the treatment of HNSCC.
- Li, Chenglong,Lin, Feng,Lin, Renyu,Liu, Zhoudi,Wang, Yi,Xia, Yiqun,Yan, Tao,Zhang, Xi,Zhang, Ziheng,Zhao, Leping
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Read Online
- Synthesis of novel 4-Boc-piperidone chalcones and evaluation of their cytotoxic activity against highly-metastatic cancer cells
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In this study, six curcuminoids containing a tert-butoxycarbonyl (Boc) piperidone core were successfully synthesized, five of them are novel compounds reported here for the first time. These compounds were prepared through an aldolic condensation by adding tetrahydropyranyl-protected benzaldehydes or substituted benzaldehyde to a reaction mixture containing 4-Boc-piperidone and lithium hydroxide in an alcoholic solvent. A 44–94% yield was obtained supporting the developed methodology as a good strategy for the synthesis of 4-Boc-piperidone chalcones. Cytotoxic activity against LoVo and COLO 205 human colorectal cell lines was observed at GI50 values that range from 0.84 to 34.7 μg/mL, while in PC3 and 22RV1 human prostate cancer cell lines, GI50 values ranging from 17.1 to 22.9 μg/mL were obtained. Results from biochemical assays suggest that the cytotoxicity of the 4-Boc-piperidone chalcones can be linked to their ability to induce apoptosis, decrease the activity of NFκB and cellular proliferation. Our findings strongly support the potential of Boc-piperidone chalcones as novel cytotoxic agents against highly-metastatic cancer cells.
- Ocasio-Malavé, Carlimar,Donate, Metsiel J.,Sánchez, María M.,Sosa-Rivera, Jesús M.,Mooney, Joseph W.,Pereles-De León, Tomás A.,Carballeira, Néstor M.,Zayas, Beatriz,Vélez-Gerena, Christian E.,Martínez-Ferrer, Magaly,Sanabria-Ríos, David J.
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supporting information
(2019/11/29)
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- Application of monocarbonyl curcumin compound in preparation of YAP protein antagonistic drug
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The invention discloses application of a monocarbonyl curcumin compound in the preparation of a YAP protein antagonistic drug. The monocarbonyl curcumin compound has an excellent antitumous effect, and further provides application in the specific targeting tumor treatment by reconstructing an unstable B-diketone group and phenolic hydroxyl group in the curcumin matrix structure, performing C design synthesis on the matrix curcumin under the alkaline condition and having high affinity combined with a YAP protein.
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Paragraph 0024; 0027; 0028
(2019/07/08)
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- STYRYLBENZOTHIAZOLE DERIVATIVES AND USES IN IMAGING
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This disclosure relates to styrylbenzothiazole derivatives for use as in vivo imaging agents for the diagnosis of Parkinson's disease (PD) or other degenerative disorders or conditions of the central nervous system. Early diagnosis is particularly advantageous as neuroprotective treatment can be applied to healthy neural cells to delay or even prevent the onset of debilitating clinical symptoms.
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Page/Page column 5; 38
(2019/12/04)
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- 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue and applications thereof
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The invention discloses a 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue and applications thereof. The structure of the 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue is represented by the formula (I) shown in the description. In the formula (I), R1 is independently selected from various alkoxyl, hydroxyl, various halogens, trifluoromethyl, or nitro. According to the invention,a plurality of experimental studies are carried out aiming at the technical field of the 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue taking substituted chalcone as a parent nucleus structure, a plurality of design, synthesis and pharmacological activity screening are carried out on the 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue taking substituted chalcone as a parent nucleus structure, and then the 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue taking substituted chalcone as a parent nucleus structure is obtained. The 2-sub-(3-methoxyl-4-hydroxyl)-benzyl-1-indanone analogue of the invention has highly efficient and broad-spectrum anti-inflammatory use.
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Paragraph 0036; 0039
(2018/09/29)
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- Synthesis, biological evaluation, QSAR and molecular dynamics simulation studies of potential fibroblast growth factor receptor 1 inhibitors for the treatment of gastric cancer
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Accumulating evidence suggests that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. Based on our previous discovery of two non-ATP competitive FGFR1 inhibitors, A114 and A117, we designed and screened a series of compounds with the framework of bisaryl-1,4-dien-3-one. Among them, D12 and D15 exhibited the most potent FGFR1 inhibitory activity, which was ATP-independent. Furthermore, a quantitative structure-activity relationship analysis of 41 analogs demonstrated that the specific structural substitutions alter their bioactivities. Molecular docking and dynamics simulation analysis indicated the hydrophobic interaction at the FGFR1-D12/D15 interaction was dominant. Evaluation for anti-gastric cancer efficacy of D12 and D15 indicated effective inhibition of cell proliferation, apoptosis induction and cell cycle arrest. Thus, these two FGFR1 inhibitors have therapeutic potential in the treatment of gastric cancer, and this study provides will contribute to the rational design of novel non-ATP competitive FGFR1 inhibitors.
- Ying, Shilong,Du, Xiaojing,Fu, Weitao,Yun, Di,Chen, Liping,Cai, Yuepiao,Xu, Qing,Wu, Jianzhang,Li, Wulan,Liang, Guang
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p. 885 - 899
(2017/02/18)
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- Selective hydrogenation of conjugated unsaturated ketones containing a hydroxyaryl substituent in the β-position
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A high selectivity was achieved in the Ni2B-catalyzed hydrogenation of α,β-unsaturated ketones containing a hydroxyaryl (phenolic) substituent in the β-position. The developed hydrogenation procedure was used to synthesize natural compounds of the phenylpropane series and their structural analogs.
- Kovalenko,Pratsko
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- Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer's disease
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Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aβ), glycogen synthase kinase 3β (GSK-3β) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3β (IC50 = 24.36 ± 0.01 μM) and Aβ42 self-aggregation (IC50 = 9.0 ± 1.4 μM), to chelate copper (II) and to act as exceptionally strong radical scavenger (kinh = 6.8 ± 0.5 · 105 M?1s?1) even in phosphate buffer at pH 7.4 (kinh = 3.2 ± 0.5 · 105 M?1s?1). Importantly, compound 3 showed high-predicted blood-brain barrier permeability, did not exert any significant cytotoxic effects in immature cortical neurons up to 50 μM and showed neuroprotective properties at micromolar concentration against toxic insult induced by glutamate.
- De Simone, Angela,Bartolini, Manuela,Baschieri, Andrea,Apperley, Kim Y.P.,Chen, Huan Huan,Guardigni, Melissa,Montanari, Serena,Kobrlova, Tereza,Soukup, Ondrej,Valgimigli, Luca,Andrisano, Vincenza,Keillor, Jeffrey W.,Basso, Manuela,Milelli, Andrea
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p. 378 - 389
(2017/08/21)
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- Synthesis and Cytotoxic Evaluation of Monocarbonyl Analogs of Curcumin as Potential Anti-Tumor Agents
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(Table Presented) A series of mono-carbonyl curcumin analogs with different substituents at the 4/4′-position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines using a methyl thiazolyl tetrazolium assay. Several of the curcumin analogs, especially B114, exhibited a wide-spectrum of anti-tumor properties in all tested cell lines, indicating their potential in as anti-cancer lead compounds. Further toxicity testing in the NRK-52E kidney cell line revealed that the analogs A111, A113, and B114 had comparable or higher safety than curcumin. These data suggested that the introduction of appropriate substituents in the 4/4′-positions could be a promising approach for curcumin-based drug design.
- Pan, Zheer,Chen, Chengwei,Zhou, Yeli,Xu, Feng,Xu, Yaozeng
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- Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines
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The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50 = 12.01 M and 8c, IC50 = 4.86 μM) and U937 (8b, IC50 = 3.44 μM and 8c, IC50 = 1.65 μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50 = 0.78 μM and 15b, IC50 = 1.9 μM while U937: 15a, IC50 = 0.95 μM and 15b, IC50 = 0.92 μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.
- Mohd Aluwi, Mohd Fadhlizil Fasihi,Rullah, Kamal,Yamin, Bohari M.,Leong, Sze Wei,Abdul Bahari, Mohd Nazri,Lim, Sock Jin,Mohd Faudzi, Siti Munirah,Jalil, Juriyati,Abas, Faridah,Mohd Fauzi, Norsyahida,Ismail, Nor Hadiani,Jantan, Ibrahim,Lam, Kok Wai
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p. 2531 - 2538
(2016/07/07)
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- Synthesis and biological evaluation of novel semi-conservative monocarbonyl analogs of curcumin as anti-inflammatory agents
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Curcumin, a natural product, has been shown to exhibit notable anti-inflammatory activities. However, the clinical application of curcumin was restricted by its poor stability and bioavailability. We have reported a series of monocarbonyl analogs of curcumin (MACs) previously. In the present study, we synthesized 32 semi-conservative MACs and evaluated their anti-inflammatory effects in RAW 264.7 macrophages. Most of them showed enhanced abilities to inhibit the lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α). The preliminary structure-activity relationship was discussed and the preliminary anti-inflammatory mechanism was also explored. The most potent analog compound, WZ35, exhibits significant protection against LPS-induced death in septic mice. These findings suggest that this kind of curcumin derivative may be used to develop promising anti-inflammatory agents to treat inflammatory diseases.
- Wang, Zhe,Zou, Peng,Li, Chenglong,He, Wenfei,Xiao, Bing,Fang, Qilu,Chen, Wenbo,Zheng, Suqing,Zhao, Yunjie,Cai, Yuepiao,Liang, Guang
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p. 1328 - 1339
(2015/07/15)
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- New chalcones containing nucleosides exhibiting in vitro anti-cancer activities
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Twenty-one new chalcones 9a-m (excluding 9e, 9j and 9l) and 10a-m (excluding 10j and 10l), containing nucleobases were synthesized from 2'-hydroxyacetophenone (1) by the reactions including chloromethylation, nucleophilic substitution with thymine and uracil, and Claisen-Schmidt reactions. These new chalcones were evaluated for in vitro cytotoxicity against five human cancer cell lines: SK-LU-1, Hep-G2, MCF7, SW480 and P388. The results showed that most of the tested chalcones exhibited inhibitory activity against five cancer cell lines except 10h, and 10i. Among the synthesized chalcones, compound 10c exhibited most potent cytotoxicity against MCF-7, SK-LU-1, SW480, HepG2 and P388 with IC50 values of 4.42, 4.81, 5.27, 3.67 and 4.11μg/mL, respectively.
- Van Chinh, Luu,Hung, Truong Ngoc,Nga, Nguyen Thi,Phong, Le,Huong, Le Mai,Ha, Tran Thi Hong,Kim, Soo Un,Vu, Tran Khac
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p. 534 - 545
(2014/05/20)
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- Synthesis, cytotoxicity against human oral cancer KB cells and structure-activity relationship studies of trienone analogues of curcuminoids
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A general method for the synthesis of substituted (1E,4E,6E)-1,7- diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9-20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure-activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study.
- Chuprajob, Thipphawan,Changtam, Chatchawan,Chokchaisiri, Ratchanaporn,Chunglok, Warangkana,Sornkaew, Nilubon,Suksamrarn, Apichart
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supporting information
p. 2839 - 2844
(2014/06/10)
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- Functionalized curcumin analogs as potent modulators of the Wnt/β-catenin signaling pathway
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Osteosarcoma is a primary bone malignancy with aggressive metastatic potential and poor prognosis rates. In our earlier work we have investigated the therapeutic potential of curcumin as an anti-invasive agent in osteosarcoma by its ability to regulate the Wnt/β-catenin signaling pathway. However, the clinical use of curcumin is limited owing to its low potency and poor pharmacokinetic profile. In this study, an attempt was made to achieve more potent Wnt inhibitory activity in osteosarcoma cells by carrying out synthetic chemical modifications of curcumin. We synthesized a total of five series consisting of 43 curcumin analogs and screened in HEK293T cells for inhibition of β-catenin transcriptional activity. Six promising analogs, which were 6.5- to 60-fold more potent than curcumin in inhibiting Wnt activity, were further assessed for their anti-invasive activity and Wnt inhibitory mechanisms. Western blot analysis showed disruption of β-catenin protein nuclear translocation following treatment with analogs 2f, 3c and 4f. Using transwell assays, we also found that these compounds were more potent than 1a (curcumin) in impeding the invasion of osteosarcoma cells, possibly through suppressing MMP-9 activity. Structure-activity-relationship studies revealed that Wnt inhibitory effects could be enhanced by shortening and restraining the flexibility of the 7-carbon linker moiety connecting the terminal aromatic rings of curcumin and substituting both rings with appropriate substituents. Our results demonstrate that the synthesized curcumin analogs are more potent Wnt inhibitors in osteosarcoma cell lines as compared to parental curcumin and are good lead compounds for further development. Future in vivo tests with these compounds will define their therapeutic potentials as promising drug candidates for clinical treatment of osteosarcoma.
- Leow, Pay-Chin,Bahety, Priti,Boon, Choon Pei,Lee, Chong Yew,Tan, Kheng Lin,Yang, Tianming,Ee, Pui-Lai Rachel
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- Multitarget-directed benzylideneindanone derivatives: Anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease
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A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ 1-42) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC 50 of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ1-42 aggregation (80.1%), and MAO-B (IC50 = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ1-42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.
- Huang, Ling,Lu, Chuanjun,Sun, Yang,Mao, Fei,Luo, Zonghua,Su, Tao,Jiang, Huailei,Shan, Wenjun,Li, Xingshu
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p. 8483 - 8492,10
(2020/09/15)
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- NOVEL STILBENE ANALOGS
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The present invention relates to Stilbene derivatives of the general formula I or a pharmaceutically acceptable salt thereof have properties such as high water solubility, bioavailability and effective as carcinostatics.
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Page/Page column 8; 9
(2010/05/13)
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- Functionalized aurones as inducers of NAD(P)H:quinone oxidoreductase 1 that activate AhR/XRE and Nrf2/ARE signaling pathways: Synthesis, evaluation and SAR
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The chemopreventive potential of functionalized aurones and related compounds as inducers of NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) are described. Several 4,6-dimethoxy and 5-hydroxyaurones induced NQO1 activity of Hepa1c1c7 cells by 2-fold at submicromolar concentrations, making these the most potent inducers to be identified from this class. Mechanistically, induction of NQO1 was mediated by the activation of AhR/XRE and Nrf2/ARE pathways, indicating that aurones may be mixed activators of NQO1 induction or agents capable of exploiting the proposed cross-talk between the AhR and Nrf2 gene batteries. QSAR analysis by partial least squares projection to latent structures (PLS) identified size parameters, in particular those associated with non-polar surface areas, as an important determinant of induction activity. These were largely determined by the substitution on rings A and B. A stereoelectronic role for the exocyclic double bond as reflected in the E LUMO term was also identified. The electrophilicity of the double bond or its effect on the conformation of the target compound are possible key features for induction activity.
- Lee, Chong-Yew,Chew, Eng-Hui,Go, Mei-Lin
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experimental part
p. 2957 - 2971
(2010/09/03)
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- Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues
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Curcuminoids have been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. Since it has been suggested that the seven-carbon β-diketone linker in curcumin is responsible for its instability, nine mono-carbonyl five-carbon linker containing analogues were designed and synthesized. Their bioactivity against lipopolysaccharide-induced TNF-α amd IL-6 secretion was evaluated by using mouse J774.1 macrophages. The results showed that the 3′-methoxyl plays an important role in bioactivity and cyclohexanone containing analogues exhibited stronger inflammatory inhibition than acetone and cyclopentanone analogues. Subsequently the most active analogue 3c was determined using single-crystal X-ray diffraction. X-ray analysis and comparison with curcumin reveals that the presence of cyclohexanone in 3c, which remotely resembles the 6-membered ring in the enol tautomer in curcumin, may play an important role in the bioactivity. It is suggested that five-carbon linker analogues containing a cyclohexane ring which are synthetically assessable may be pharmacologically important.
- Liang, Guang,Yang, Shulin,Zhou, Huiping,Shao, Lili,Huang, Kexin,Xiao, Jian,Huang, Zhifeng,Li, Xiaokun
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experimental part
p. 915 - 919
(2009/09/08)
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- Synthesis and anti-bacterial properties of mono-carbonyl analogues of curcumin
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The synthesis of three series of curcumin analogues with mono-carbonyl is described. Their in vitro antibacterial activities against seven Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the aryl ring and the space structure of the linking strain were discussed. It was observed that part of the derivatives displayed significant activity when compared with curcumin and most of them exhibited activity against the ampicillin-resisted Enterobacter cloacae. Compounds A12, B09, B13, B14 and C09 show remarkable antibacterial activity in vitro. The result showed that heterocycle or long-chain substituents may enhance the activity of curcumin analogues.
- Liang, Guang,Yang, Shulin,Jiang, Lijuan,Zhao, Yu,Shao, Lili,Xiao, Jian,Ye, Faqing,Li, Yueru,Li, Xiaokun
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p. 162 - 167
(2008/09/19)
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- Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin
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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 aldo-keto 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.
- Liang, Guang,Li, Xiaokun,Chen, Li,Yang, Shulin,Wu, Xudong,Studer, Elaine,Gurley, Emily,Hylemon, Phillip B.,Ye, Faqing,Li, Yueru,Zhou, Huiping
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p. 1525 - 1529
(2008/09/19)
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- An efficient and facile synthesis of capsaicin-like compounds as agonists of the TRPV1 receptor
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A new versatile synthetic route is described for the preparation of capsaicin-like molecules which contain an α-hydroxy ketone functional group mimicking the amide functional group in the capsaicin structure. The key reaction in this synthesis was the formation of α-(dimethylamino) alkanenitriles as intermediates. These nitriles were successfully prepared from both aliphatic and aromatic aldehydes by reaction with dimethylamine and aqueous sodium cyanide. Treatment of the nitriles with lithium diisopropylamide (LDA) followed by reaction with various aldehydes led to the formation of α-hydroxy ketone compounds, examples of which include 2-hydroxy-1-(4- hydroxy-3-methoxyphenyl)dodecan-3-one, (5R)- and (5S)-2-hydroxy-1-(4-hydroxy-3- methoxyphenyl)-5,9-dimethyldec-8-en-3-one, representing novel capsaicin-like molecules. Formation of (4-benzyloxy-3-methoxyphenyl)-acetaldehyde was also described from the Wittig reaction of 4-benzyloxy-3-methoxybenzadehyde with an ylide reagent (methoxymethyl)triphenylphosphonium bromide followed by acid hydrolysis to form the title compound. This aldehyde represents a useful precursor for the synthesis of capsaicin-like structures. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Tran, Van H.,Kantharaj, Ravi,Roufogalis, Basil D.,Duke, Colin C.
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p. 2970 - 2976
(2007/10/03)
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- Pharmaceutical compositions useful in prevention and treatment of beta-Amyloid protein-induced disease
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The invention provides methods for treating beta-Amyloid protein-induced disease, pharmaceutical compositions and compounds useful for the same, and the use of these compounds for the manufacture of a medicament for treating the same. More particularly, the invention relates to the use of natural product compounds isolated from turmeric, gingko biloba, and ginger, and synthetic chemical analogues thereof, for the treatment of a beta-Amyloid protein-induced disease.
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Page/Page column 19; sheet 4
(2008/06/13)
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- Chemotherapy of leishmaniasis part II: Synthesis and bioevaluation of substituted arylketene dithioacetals as antileishmanial agents
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Some novel aryl substituted ketene dithioacetals 6 (a-d), 9 (a-c) and 10 (a-c) have been synthesized using novel synthetic methods. The compounds were screened against Leishmania donovani in hamsters for their activity profile. Some of the compounds inhibited 50-65% parasite growth at 50mg kg-1 × 5 days.
- Pandey, Susmita,Suryawanshi,Gupta, Suman,Srivastava
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p. 751 - 756
(2007/10/03)
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- Low-valent titanium mediated synthesis of hydroxystilbenoids: Some new observations
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A series of phenolic stilbenoids possessing different numbers and positions of hydroxylation, partial methoxyl substituents and nature of olefinic moieties has been synthesized by McMurry coupling. It is found that the McMurry coupling of the phenolic aldehydes furnishes the dihydrostilbenes via an in situ hydrogenation, while the phenolic ketones give the stilbenes. Interestingly, the study also reveals that the low-valent titanium reagent (TiCl 3-Zn-THF) could selectively depyranylate phenolic -OTHP function without affecting alcoholic -OTHP group.
- Shadakshari,Rele,Nayak,Chattopadhyay
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p. 1934 - 1938
(2007/10/03)
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- Efficient tetrahydropyranylation of phenols and alcohols catalyzed by supported Mo and W Keggin heteropolyacids
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The protection of phenols as tetrahydropyranyl acetals is studied using supported Keggin heteropolyacids as catalysts, specifically molybdophosphoric or tungstophosphoric acids supported on silica. Phenol tetrahydropyranyl acetals are obtained in short times at room temperature with excellent yields. Protection of alcohols is also performed under mild conditions using both supported heteropolyacids, with yields ranging between good and quantitative. The reactions are clean and their workup is very simple. The use of these solid catalysts allows replacing the usual soluble inorganic acids, contributing to waste reduction.
- Romanelli,Vazquez,Pizzio,Caceres,Blanco,Autino
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p. 1359 - 1365
(2007/10/03)
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- Efficient method for tetrahydropyranylation/depyranylation of phenols and alcohols using a solid acid catalyst with Wells-Dawson structure
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A simple and efficient procedure to form 2-tetrahydropyranyl acetals of phenols and alcohols is reported. Wells-Dawson heteropolyacid catalyst is used both in bulk form or supported on silica, reaction conditions include room temperature and toluene as solvent. Fast deprotection of THP-acetals can be attained by mere change of the solvent using THF-1% MeOH. In both reactions the supported catalyst is easily recoverable and reusable, and the yields are good to excellent.
- Romanelli, Gustavo P.,Baronetti, Graciela,Thomas, Horacio J.,Autino, Juan C.
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p. 7589 - 7591
(2007/10/03)
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- Synthesis and aromatase inhibitory activity of flavanones
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Purpose. Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern. Methods. A series of flavanones was prepared by cyclisation of 2′hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-3H]-androstenedione as substrate. Results. Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3′ and/or 4′ enhanced the anti-aromatase activity; thus, 3′,4′-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used. Conclusions. These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.
- Pouget,Fagnere,Basly,Besson,Champavier,Habrioux,Chulia
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p. 286 - 291
(2007/10/03)
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- Total synthesis of calebin-A, preparation of its analogues, and their neuronal cell protectivity against β-amyloid insult
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A total synthesis of Calebin-A (1), a novel curcuminoid isolated from turmeric (Curcuma longa, Zingiberaceae) that has been demonstrated to protect neuronal cells from β-amyloid insult, was successfully achieved in four steps. Elaborating on this synthetic route, 13 analogues were prepared for a structure-activity relationship (SAR) study. It was found that the parent compound 1 and derivatives 21, 28, and 30 protect PC12 rat pheocromocytoma and IMR-32 human neuroblastoma cells from β-amyloid(25-35) insult. These results suggest that hydroxy group at para-position is most critical for the expression of biological activity.
- Kim, Darrick S.H.L,Kim, Jin Yung
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p. 2541 - 2543
(2007/10/03)
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- 3,4-Dihydroxychalcones as potent 5-lipoxygenase and cyclooxygenase inhibitors
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A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4- dihydroxychalcones with hydroxy or alkoxy groups exhibited optimal inhibition of cyclooxygenase. We found that 2',5'-dimethoxy-3,4-dihydroxychalcone (37; HX-0836) inhibited cyclooxygenase to the same degree as flufenamic acid and 5-lipoxygenase, more than quercetin. Finally, these active inhibitors of 5- lipoxygenase inhibited arachidonic acid-induced mouse ear edema more than phenidone.
- Sogawa,Nihro,Ueda,Izumi,Miki,Matsumoto,Satoh
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p. 3904 - 3909
(2007/10/02)
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- Synthesis of (E)-4-(3-hydroxy-1-propenyl)-2-methoxyphenol-bovine serum albumin conjugate: A novel hapten-protein conjugate
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The synthesis of a novel hapten-carrier protein conjugate, (E)-4-(3-hydroxy-1-propenyl)-2-methoxyphenol-bovine serum albumin (coniferyl alcohol-BSA), is described. This method is particularly useful for the synthesis of monolignol-protein conjugates by linking β-C of monolignol side-chain and the amino group of protein through a -CH2CO- linker. Coniferyl alcohol-BSA conjugate was used to raise rabbit polyclonal antibodies as a probe for the further investigation of the biogenesis of coniferyl alcohol in plant cells by an immunoelectron microscopy technique.
- Lee, Dian Y.,Chiang, Vincent L.
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p. 5255 - 5258
(2007/10/02)
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