10263-19-1Relevant articles and documents
Radiosensitization of human pancreatic cancer by piperlongumine analogues
Ma, Hao,Wu, Yuelin,Zhang, Wannian,Zhang, Huojun,Miao, Zhenyuan,Zhuang, Chunlin
, p. 1197 - 1201 (2021)
Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by 2 months in combination with gemcitabine. However, prognosis and survival improvement remain unsatisfactory, and effective therapies are urgently needed. Piperlongumine has been demonstrated to have therapeutic potentials against various cancers. In this study, we synthesized a series of piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as effective radiosensitizers in pancreatic cancer. Two compounds enhanced the radiosensitivity of Panc-1 and SW1990 cells. In a pancreatic bi-flank xenograft tumor model, they significantly inhibited tumor growth. Piperlongumine derivatives could induce reactive oxygen species (ROS) expression and regulate the Keap1-Nrf2 protective pathway with enhancement of radiation-induced DNA damage, G2/M-phase cell cycle arrest, and apoptosis. Collectively, our data offer a proof of concept for the use of piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.
Synthesis and biological evaluation of N-cinnamoyl and mandelate metformin analogues
Anitha Kumari,Bharathi,Prabhu,Ponnudurai
, p. 1895 - 1898 (2016)
A series of N,N-dimethyl-N1-[3-(substituted phenyl)-1-oxo-2-propenyl]biguanides were synthesized by coupling a solution of metformin in pyridine with different cinnamoyl chloride derivatives in ether for 3 h in addition to synthesis of some five molecules of metformin-mandelates. All the synthesized cinnamoyl metformins and a few metformin-mandelates were characterized by IR, NMR and Mass spectroscopic techniques. All the synthesized compounds were also evaluated for their antioxidant activity by DPPH scavenging method and nitric oxide scavenging method. All the compounds exhibited good antioxidant activity.
Synthetic analogue of the natural product piperlongumine as a potent inhibitor of breast cancer cell line migration
Valli, Marilia,Altei, Wanessa,Dos Santos, Ricardo N.,De Lucca, Emilio C.,Dessoy, Marco A.,Pioli, Renan M.,Cotinguiba, Fernando,Cachet, Xavier,Michel, Sylvie,Furlan, Maysa,Dias, Luiz C.,Andricopulo, Adriano D.,Bolzani, Vanderlan S.
, p. 475 - 484 (2017)
Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC50 of 3.0 ± 1.0 μM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC50 of 1.5 ± 1 μM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4.
Structure–Activity relationship of piplartine and synthetic analogues against schistosoma mansoni and cytotoxicity to mammalian cells
Campelo, Yuri,Ombredane, Alicia,Vasconcelos, Andreanne G.,Albuquerque, Lucas,Moreira, Daniel C.,Plácido, Alexandra,Rocha, Jefferson,Fokoue, Harold Hilarion,Yamaguchi, Lydia,Mafud, Ana,Mascarenhas, Yvonne P.,Delerue-Matos, Cristina,Borges, Tatiana,Joanitti, Graziella A.,Arcanjo, Daniel,Kato, Massuo J.,Kuckelhaus, Selma A. S.,Silva, Marcos P. N.,de Moraes, Josué,Leite, José Roberto S. A.
, (2018)
Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure–function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5–10 μM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 μM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine.
Synthetic 2′,5′-dimethoxychalcones as G2/M arrest-mediated apoptosis-inducing agents and inhibitors of nitric oxide production in rat macrophages
Wei, Bai-Luh,Teng, Chi-Huang,Wang, Jih-Pyang,Won, Shen-Jeu,Lin, Chun-Nan
, p. 660 - 668 (2007)
In an effort to develop novel antitumor or chemopreventive agents, a series of 2′,5′-dimethoxychalcone derivatives were prepared by Claisen-Schmidt condensation of appropriate acetophenones with suitable aromatic aldehyde. In vitro screening revealed low micromolar activity (IC50) against several human cancer lines. Activity in MCF-7 cells correlated with the ability to induce G2/M arrest-mediated apoptosis following drug treatment by the most potent agent, 8, an observation further reinforced by fluorescence microscopy. Compounds 3, 8, and 10 showed potent inhibitory effect on NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage-like cells. The present results demonstrated that 3, 8, and 10 are potential anti-inflammatory and cancer chemopreventive agents.
Keto-enol-based modification on piperlongumine to generate a potent Cu(II) ionophore that triggers redox imbalance and death of HepG2 cells
Dai, Fang,Yuan, Cui-Hong,Ji, Yuan,Du, Yu-Ting,Bao, Xia-Zhen,Wu, Ling-Xi,Jin, Xiao-Ling,Zhou, Bo
, p. 124 - 132 (2018)
Altered redox status including higher levels of copper in cancer cells than in normal cells inspired many researchers to develop copper ionophores targeting this status. We have recently found that flavon-3-ol (3-HF) works as a potent Cu(II) ionophore by virtue of its keto-enol moiety. To further emphasize the significance of this moiety for developing Cu(II) ionophores, we herein designed a β-diketo analog of piperlongumine, PL-I, characterized by the presence of high proportion of the keto-enol form in dimethylsulfoxide and chloroform, and identified its keto-enol structure by NMR and theoretical calculations. Benefiting from deprotonation of its enolic hydroxyl group, this molecule is capable of facilitating the transport of Cu(II) through cellular membranes to disrupt redox homeostasis of human hepatoma HepG2 cells and trigger their death.
Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents
Liu, Sheng,Wei, Wanxing,Li, Yubin,Liu, Xu,Cao, Xiaoji,Lei, Kechan,Zhou, Min
, p. 473 - 482 (2015)
A series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the synthesized derivatives showed effective anti-HBV activity. Of these compounds, compound 4c-1 showed the most potent anti-HBV activity, demonstrating potent inhibitory effect not only on the secretion of HBsAg (IC50 = 14.18 μM, SI = 17.85) and HBeAg (IC50 = 6.20 μM, SI = 40.82) secretion but also HBV DNA replication (IC50 = 23.43 μM, SI = 10.80). The structureeactivity relationships (SARs) of phenylpropanoid derivatives had been discussed, which were useful for phenylpropanoid derivatives to be explored and developed as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site were carried out to explore the molecular interactions and a molecular target for activity of phenylpropanoid derivatives with the protein using a moe-docking technique. This study identified a new class of potent anti-HBV agents.
Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity
Shi, Jing Bo,Tang, Wen Jian,Qi, Xing Bao,Li, Rong,Liu, Xin Hua
, p. 889 - 896 (2015)
A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 μM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.
Synthesis and Spectroscopic Analysis of Piperine- And Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins
Cornelio, Marinonio L.,Jones, Alan M.,Le Duff, Cécile S.,Povinelli, Ana Paula R.,Tang, Bridget,Zazeri, Gabriel
, (2020)
Inspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide piperine analogues including the use of two-dimensional (2D) 15N-based spectroscopy nuclear magnetic resonance (NMR) spectroscopy. Prior investigations demonstrated promising results from these scaffolds for the inhibition of inflammatory response via downregulation of the IL-1β and NF-κB pathway. However, the molecular interaction of these molecules with their protein targets remains unknown. Ab initio calculations revealed the electronic density function map of the molecules, showing the effects of structural modification in the electronic structure. Finally, molecular interactions between the synthesized molecules and the proteins IL-1β and NF-κB were achieved. Docking results showed that all the analogues interact in the DNA binding site of NF-κB with higher affinity compared to the natural products and, with the exception of 9a and 9b, have higher affinity than the natural products for the binding site of IL-1β. Specificity for the molecular recognition of 3a, 3c and 9b with IL-1β through cation–π interactions was determined. These results revealed 3a, 3c, 4a, 4c and 10 as the most promising molecules to be evaluated as IL-1β and NF-κB inhibitors.
Synthesis, in vitro and in vivo antitumor activity of scopoletin-cinnamic acid hybrids
Li, Linhu,Zhao, Peng,Hu, Jinglin,Liu, Jinhong,Liu, Yan,Wang, Zhiqiang,Xia, Yufeng,Dai, Yue,Chen, Li
, p. 300 - 307 (2015)
A series of hybrids of scopoletin and substituted cinnamic acid were designed, synthesized and evaluated in vitro and in vivo against five human tumor cell lines [MCF-7, MDA-MB-231, A549, HCT-116, and HeLa] with doxorubicin as the positive control. Compounds 17a, 17b, 17c and 17g exhibited potent cytotoxic activity. Especially, compound 17b displayed broad spectrum activity with IC50 values ranging from 0.249 μ1/4M to 0.684 μ1/4M. Moreover, in a preliminary pharmacological study, 17b not only remarkably induced cellular apoptosis, but also clearly induced A549 cells cycle arrest at S phase. In vivo study showed that 17b significantly suppressed tumor growth in a dose-dependent manner without causing the loss of the mean body weight of mice, which was superior to doxorubicin. These preliminary results indicate that 17b is an optimal anti-cancer leading compound and merit further structural modification.
Synthesis and biological evaluation of piperlongumine derivatives as potent anti-inflammatory agents
Seo, Young Hwa,Kim, Jin-Kyung,Jun, Jong-Gab
, p. 5727 - 5730 (2014)
Piperlongumine (PL) and its derivatives were synthesized by the direct reaction between acid chloride of 3,4,5-trimethoxycinnamic acid and various amides/lactams. Later their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. Of the piperlogs prepared in this study, the maximum (91%) inhibitory activity was observed with PL (IC50 = 3 μM) but showed cytotoxicity whereas compound 3 (IC50 = 6 μM) which possess α,β-unsaturated γ-butyrolactam moiety offered good level (65%) of activity with no cytotoxicity. This study revealed that amide/lactam moiety connected to cinnamoyl group with minimum 3 carbon chain length and α,β-unsaturation is fruitful to show potent anti-inflammatory activity.
Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
Kamal, Ahmed,Bajee, Shaik,Lakshma Nayak, Vadithe,Venkata Subba Rao, Ayinampudi,Nagaraju, Burri,Ratna Reddy, Challa,Jeevak Sopanrao, Kapure,Alarifi, Abdullah
, p. 2957 - 2964 (2016)
A series of new molecules have been designed based on a hybridization approach by combining the arylcinnamide and combretastatin pharmacophores. These were synthesized and evaluated for their cytotoxic activity, effect on inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant cytotoxic activity against some representative human cancer cell lines and two of the conjugates 6i and 6p displayed potent cytotoxicity with GI50 values of 56 nM and 31 nM respectively against the human breast cancer cell line (MCF-7). SAR studies revealed that 3,4-substitution on the phenyl ring of the cinnamide moiety is beneficial for enhanced cytotoxicity. Moreover, G2/M cell cycle arrest was induced by these conjugates (6i and 6p) apart from tubulin polymerization inhibition (IC50 of 1.97 μM and 1.05 μM respectively). Further, mitochondrial membrane potential, Annexin V-FITC and caspase-9 activation assays suggested that these conjugates induce cell death by apoptosis. Docking studies revealed that these conjugates interact and bind at the colchicine binding site of the tubulin.
Synthesis and in vitro antiproliferative activities of lupanol derivatives towards human esophageal squamous carcinoma cells
Li, Weijie,Xiao, Yeyu
, (2020)
A series of lupanol derivatives were synthesized and evaluated in vitro for their inhibitory activities against three human esophageal squamous carcinoma cells lines, Eca-109, TE-1 and EC-9706. Among lupanol derivatives, seven were new compounds, and lupanol cinnamate analogues 5 and 6, hydrazone analogues 9 and 10 presented high activities towards all the tested tumour cells, even higher activities than those of doxorubicine.
Modulation of the spacer in N,N-bis(alkanol)amine aryl ester heterodimers led to the discovery of a series of highly potent P-glycoprotein-based multidrug resistance (MDR) modulators
Dei, Silvia,Braconi, Laura,Trezza, Alfonso,Menicatti, Marta,Contino, Marialessandra,Coronnello, Marcella,Chiaramonte, Niccolò,Manetti, Dina,Perrone, Maria Grazia,Romanelli, Maria Novella,Udomtanakunchai, Chatchanok,Colabufo, Nicola Antonio,Bartolucci, Gianluca,Spiga, Ottavia,Salerno, Milena,Teodori, Elisabetta
, p. 71 - 94 (2019)
In this study, a new series of N,N-bis(alkanol)amine aryl ester heterodimers was synthesized and studied. The new compounds were designed based on the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity on a multidrug-resistant leukemia cell line. All new compounds were active in the pirarubicin uptake assay on the doxorubicin–resistant erythroleukemia K562 cells (K562/DOX). Compounds bearing a linker made up of 10 methylenes showed unprecedented high reversal activities regardless of the combination of aromatic moieties. Docking results obtained by an in silico study supported the data obtained by the biological tests and a study devoted to establish the chemical stability in phosphate buffer solution (PBS) and human plasma showed that only a few compounds exhibited a significant degradation in the human plasma matrix. Ten selected non-hydrolysable derivatives were able to inhibit the P-gp-mediated rhodamine-123 efflux on K562/DOX cells, and the evaluation of their apparent permeability and ATP consumption on other cell lines suggested that the compounds can behave as unambiguous or not transported substrates. The activity of these the compounds on the transport proteins breast cancer resistance protein (BCRP) and multidrug resistance associated protein 1 (MRP1) was also analyzed. All tested derivatives displayed a moderate potency on the BCRP overexpressing cells; while only four molecules showed to be effective on MRP1 overexpressing cells, highlighting a clear structural requirement for selectivity. In conclusion, we have identified a new very powerful series of compounds which represent interesting leads for the development of new potent and efficacious P-gp-dependent MDR modulators.
Practical access to fluorescent 2,3-naphthalimide derivatives: Via didehydro-Diels-Alder reaction
Chen, Xia,Zhong, Cheng,Lu, Yuling,Yao, Meng,Guan, Zhenhua,Chen, Chunmei,Zhu, Hucheng,Luo, Zengwei,Zhang, Yonghui
supporting information, p. 5155 - 5158 (2021/05/31)
A practical and efficient approach for the synthesis of fluorescent 2,3-naphthalimide derivatives has been developed from readily available starting materials via an intramolecular didehydro-Diels-Alder reaction, which proceeded well under room temperature, exhibiting a wide substrate scope and good functional group tolerance. The practicability of this methodology has been verified by one-step synthesis of the environmentally sensitive fluorophore 6-DMN on a gram scale with a shorter time, fewer steps and less waste disposal, and without the utilization of toxic transition metals. The present experimental and computational studies support the crucial role of the propiolimide moiety in the transformation.
