- Radiosensitization of human pancreatic cancer by piperlongumine analogues
-
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.
- Ma, Hao,Wu, Yuelin,Zhang, Wannian,Zhang, Huojun,Miao, Zhenyuan,Zhuang, Chunlin
-
-
Read Online
- Mild, Metal-Free and Protection-Free Transamidation of N-Acyl-2-piperidones to Amino Acids, Amino Alcohols and Aliphatic Amines and Esterification of N-Acyl-2-piperidones
-
Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials. We report a highly selective method for the synthesis of amides via transamidation process. Transamidation of N-acyl-2-piperidones with a broad range of amines is demonstrated under exceedingly mild and metal-free reaction condition that relies on the amide bond twist to weaken the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in short reaction times (30–90 min) with good yields. Considerable variation is tolerated with both amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and hydroxyl groups (dopamine, tyramine, etc.) are well tolerated which are otherwise problematic under the metal-catalyzed protocol. Our current method is applicable for transamidation of both alkyl and aryl-N-acyl-2-piperidones. The practical value of the method is highlighted by the synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In the absence of nucleophilic amines, N-acyl-2-piperidones undergoes esterification with EtOH at elevated temperature. Single crystal X-ray analysis of an N-acyl-2-piperidone shows amide bond twist, τ = –20.39° and pyramidalization, χN = –11.73°. This weakens the amidic conjugation and might be the factor controlling the reactivity and selectivity of these imides. We envision that the N-acyl-2-piperidone scaffold would be useful in the synthesis of pharmaceuticals and materials.
- Subramani, Muthuraman,Rajendran, Saravana Kumar
-
-
Read Online
- Synthesis and biological evaluation of N-cinnamoyl and mandelate metformin analogues
-
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.
- Anitha Kumari,Bharathi,Prabhu,Ponnudurai
-
-
Read Online
- Discovery and development of novel pyrimidine and pyrazolo/thieno-fused pyrimidine derivatives as potent and orally active inducible nitric oxide synthase dimerization inhibitor with efficacy for arthritis
-
In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on “Hit” we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 μM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 μM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 μM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.
- Chen, Liu Zeng,Shu, Hai Yang,Wu, Jing,Yu, Yun Long,Ma, Duo,Huang, Xin,Liu, Ming Ming,Liu, Xin Hua,Shi, Jing Bo
-
-
Read Online
- Synthetic analogue of the natural product piperlongumine as a potent inhibitor of breast cancer cell line migration
-
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.
- 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.
-
-
Read Online
- First round of a focused library of cholera toxin inhibitors
-
C-Galactosides have been used as scaffolds to design a library of non-hydrolysable inhibitors of cholera toxin (CT). Test elements from the library were synthesized and found to inhibit CT binding to an asialofetuin-coated SPR chip with micromolar affinity. Preliminary results are reported.
- Podlipnik, Crtomir,Velter, Ingrid,Ferla, Barbara La,Marcou, Gilles,Belvisi, Laura,Nicotra, Francesco,Bernardi, Anna
-
-
Read Online
- Structure–Activity relationship of piplartine and synthetic analogues against schistosoma mansoni and cytotoxicity to mammalian cells
-
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.
- 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.
-
-
Read Online
- Development of sulfonamides incorporating phenylacrylamido functionalities as carbonic anhydrase isoforms I, II, IX and XII inhibitors
-
A series of novel sulfonamides incorporating phenylacrylamido functionalities were synthesized and investigated for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The physiologically and pharmacologically relevant human (h) isoforms hCA I and II (cytosolic isozymes), as well as the transmembrane tumor-associated hCA IX and XII were included in the study. These compounds showed low nanomolar or sub-nanomolar inhibition constants against hCA II (KIs in the range of 0.50–50.5 nM), hCA IX (KIs of 1.8–228.5 nM), and hCA XII (KIs of 3.5–96.2 nM) being less effective as inhibitors of the off target isoform hCA I. A detailed structure–activity relationship study demonstrates that the nature and position of substituents present on the aromatic part of the scaffold strongly influence the inhibition of CA isoforms. As hCA II, IX and XII are involved in pathologies such as glaucoma and hypoxic, and metastatic tumors, compounds of the type reported in this work may be useful preclinical candidates.
- Angapelly, Srinivas,Ramya, P.V. Sri,Angeli, Andrea,Del Prete, Sonia,Capasso, Clemente,Arifuddin, Mohammed,Supuran, Claudiu T.
-
-
Read Online
- Synthetic 2′,5′-dimethoxychalcones as G2/M arrest-mediated apoptosis-inducing agents and inhibitors of nitric oxide production in rat macrophages
-
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.
- Wei, Bai-Luh,Teng, Chi-Huang,Wang, Jih-Pyang,Won, Shen-Jeu,Lin, Chun-Nan
-
-
Read Online
- Synthesis and biological evaluation of novel fumagillin and ovalicin analogues
-
A promising approach among the numerous efforts to cure cancer is the interruption of the tumour-induced formation of new blood vessels (angiogenesis). By suppressing angiogenesis with drugs, the tumour can neither grow to a life threatening size, nor metastasize. The natural product fumagillin 1 and the structurally related ovalicin 2 are two of the most potent anti-angiogenic compounds. Here, we report the design and synthesis of novel fumagillin and ovalicin analogues lacking reactive epoxy functionalities, which were thought to be responsible for the severe toxic side-effects observed. We also report a new synthetic approach and the determination of the anti-angiogenic properties of these compounds in endothelial cells. The Royal Society of Chemistry 2005.
- Mazitschek, Ralph,Huwe, Axel,Giannis, Athanassios
-
-
Read Online
- Keto-enol-based modification on piperlongumine to generate a potent Cu(II) ionophore that triggers redox imbalance and death of HepG2 cells
-
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.
- Dai, Fang,Yuan, Cui-Hong,Ji, Yuan,Du, Yu-Ting,Bao, Xia-Zhen,Wu, Ling-Xi,Jin, Xiao-Ling,Zhou, Bo
-
-
Read Online
- Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines
-
This work describes the total synthesis of the alkaloid cenocladamide and a concise library of nine structural analogues aiming at their evaluation against the breast cancer cell line MDA-MB-231. The most promising compound (3; IC50 = 6.6 μM) was also evaluated in a panel of seven breast cancer cell lines and two non-tumorigenic cell lines. We further conducted an initial investigation on the mechanism of action of analogue 3, which lacks the endocyclic double bond when compared to cenocladamide. The present study presents the discovery of a cenocladamide analogue with interesting cytotoxic activity, which could be useful for further optimization towards new chemotherapeutic agents for breast cancer treatment.
- Santos, Carla C. F.,Paradela, Luciana S.,Novaes, Luiz F. T.,Dias, Sandra M. G.,Pastre, Julio C.
-
-
Read Online
- Design, synthesis, biological evaluation and molecular docking studies of phenylpropanoid derivatives as potent anti-hepatitis B virus agents
-
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.
- Liu, Sheng,Wei, Wanxing,Li, Yubin,Liu, Xu,Cao, Xiaoji,Lei, Kechan,Zhou, Min
-
-
Read Online
- Design, synthesis, molecular docking studies and anti-HBV activity of phenylpropanoid derivatives
-
In this work, a series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated. Most of the synthesized derivatives showed effective anti-HBV activity. And compound 4d-3 showed the most effective anti-HBV activity, performing strong potent inhibitory not only on the secretion of HBsAg (IC50 = 58.28 μM, SI = 23.26) and HBeAg (IC50 = 97.21 μM, SI = 13.95), but also on the HBV DNA replication (IC50 = 42.28 μM, SI = 32.06). The structure-activity relationships (SARs) of the derivatives had been discussed, which were useful for developing phenylpropanoid derivatives as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site was carried out to explore the molecular interactions and a molecular target for activity and a modified assay method measuring the interaction between our derivatives and HBcAg was investigated, indicating that the HBV core protein might be their potential target for anti-HBV. This study identified a new class of potent non-nucleoside anti-HBV agents.
- Liu, Sheng,Li, Yubin,Wei, Wanxing,Wang, Kuiwu,Wang, Lisheng,Wang, Jianyi
-
-
Read Online
- Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: Synthesis and anticancer activity
-
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.
- Shi, Jing Bo,Tang, Wen Jian,Qi, Xing Bao,Li, Rong,Liu, Xin Hua
-
-
Read Online
- Novel Pyrazolo[4,3- d]pyrimidine as Potent and Orally Active Inducible Nitric Oxide Synthase (iNOS) Dimerization Inhibitor with Efficacy in Rheumatoid Arthritis Mouse Model
-
In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3-d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1H-pyrazolo[4,3-d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.
- Shi, Jing Bo,Chen, Liu Zeng,Wang, Bao Shi,Huang, Xin,Jiao, Ming Ming,Liu, Ming Ming,Tang, Wen Jian,Liu, Xin Hua
-
-
Read Online
- Synthesis and Spectroscopic Analysis of Piperine- And Piperlongumine-Inspired Natural Product Scaffolds and Their Molecular Docking with IL-1β and NF-κB Proteins
-
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.
- Cornelio, Marinonio L.,Jones, Alan M.,Le Duff, Cécile S.,Povinelli, Ana Paula R.,Tang, Bridget,Zazeri, Gabriel
-
-
Read Online
- All trans 1-(3-arylacryloyl)-3,5-bis (pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics
-
A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4-piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase III±. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies.
- Paul, Nawal K.,Jha, Mamta,Bhullar, Khushwant S.,Rupasinghe, H.P. Vasantha,Balzarini, Jan,Jha, Amitabh
-
-
Read Online
- Synthesis, in vitro and in vivo antitumor activity of scopoletin-cinnamic acid hybrids
-
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.
- Li, Linhu,Zhao, Peng,Hu, Jinglin,Liu, Jinhong,Liu, Yan,Wang, Zhiqiang,Xia, Yufeng,Dai, Yue,Chen, Li
-
-
Read Online
- Design, synthesis and biological evaluation of stereo- and regioisomers of amino aryl esters as multidrug resistance (MDR) reversers
-
Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.
- Teodori, Elisabetta,Contino, Marialessandra,Riganti, Chiara,Bartolucci, Gianluca,Braconi, Laura,Manetti, Dina,Romanelli, Maria Novella,Trezza, Alfonso,Athanasios, Asimidis,Spiga, Ottavia,Perrone, Maria Grazia,Giampietro, Roberta,Gazzano, Elena,Salerno, Milena,Colabufo, Nicola Antonio,Dei, Silvia
-
-
Read Online
- Synthesis and biological evaluation of piperlongumine derivatives as potent anti-inflammatory agents
-
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.
- Seo, Young Hwa,Kim, Jin-Kyung,Jun, Jong-Gab
-
-
Read Online
- Design and synthesis of N-acylated aza-goniothalamin derivatives and evaluation of their in vitro and in vivo antitumor activity
-
Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1- (E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2/M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.
- Barcelos, Rosimeire Coura,Pastre, Julio Cezar,Vendramini-Costa, Dbora Barbosa,Caixeta, Vanessa,Longato, Giovanna Barbarini,Monteiro, Paula Araffljo,De Carvalho, Joo Ernesto,Pilli, Ronaldo Aloise
-
-
Read Online
- Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents
-
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.
- Kamal, Ahmed,Bajee, Shaik,Lakshma Nayak, Vadithe,Venkata Subba Rao, Ayinampudi,Nagaraju, Burri,Ratna Reddy, Challa,Jeevak Sopanrao, Kapure,Alarifi, Abdullah
-
-
Read Online
- Synthesis and biological evaluation of phenylpropanoid derivatives
-
In this work, a series of oxime ether phenylpropanoid derivatives were synthesized. Their anti-hepatitis B virus (HBV) activity in HepG 2.2.15 cells was determined, and anti-cancer potential against three human cancer cell lines was evaluated. All the synthesized derivatives showed great efficiency against HBV. Compound 4d demonstrated the most effective anti-HBV activity, performing strong potent inhibitory not only on the secretion of HBsAg (IC50?=?50.45?μM, SI?=?9.18) and HBeAg (IC50?=?50.11?μM, SI?=?9.24), but also on the HBV DNA replication (IC50?=?51.80?μM, SI?=?8.94). Besides, the synthetic compounds also displayed obvious anti-cancer activity. Moreover, the docking study of all synthesized compounds inside the related protein active site was conducted to explore the molecular interactions and a molecular target for activity using a MOE-docking technique. This study identified a new class of potent anti-HBV and anti-cancer agents.
- Liu, Sheng,Li, Yubin,Wei, Wanxing,Wei, Jingchen
-
-
Read Online
- Synthesis and in vitro antiproliferative activities of lupanol derivatives towards human esophageal squamous carcinoma cells
-
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.
- Li, Weijie,Xiao, Yeyu
-
-
Read Online
- Design, Synthesis and Pharmacological Evaluation of Novel Piperlongumine derivatives as Potential Antiplatelet Aggregation Candidate
-
A series of novel piperlongumine derivatives (4a-i, 6a-i) were designed and synthesized. The inhibitory activities of platelet aggregation induced by ADP and AA in vitro have been evaluated by bron turbidimetry and liver microsomal incubated assay. The assay results show that compounds 4e and 6e exhibited remarkable potency to that of the positive control piplartine and aspirin.
- Wang, Yujun,Wang, Jie,Li, Jiaming,Zhang, Yanchun,Huang, Weijun,Zuo, Jian,Liu, Huicai,Xie, Di,Zhu, Panhu
-
-
Read Online
- 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
-
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.
- 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
-
-
Read Online
- Synthesis of sorbicillinoid analogues with anti-inflammation activities
-
Recently, we demonstrated potential anti-inflammatory effects of sorbicillinoids isolated from marine fungi. Here, we report the synthesis of a series of new sorbicillinoid analogues and assessed their anti-inflammatory activities. Our results reveal that side chain substitution with (E)-2-butenoyl, (E)-3-(4-fluorophenyl)-2-propenoyl, and (E)-3-(3,4,5-trimethoxyphenyl)-2-propenoyl significantly enhanced the inhibitory effects of the derivatives on nitric oxide (NO) production and inducible NO synthesis (iNOS) expression stimulated by lipopolysaccharides (LPS) in mouse macrophage. Further chemical derivatization shows that the monomethylresorcinol skeleton worked better than the dimethylresorcinol skeleton in inhibiting LPS-induced inflammatory response in cultured cells. Among the 29 synthesized sorbicillinoid analogues, compounds 4b and 12b exhibited the strongest anti-inflammatory activities, holding the promise of being developed into lead compounds that can be explored as potent anti-inflammation agents.
- Ding, Wenjuan,Li, Xiaosan,Tang, Jinshan,Tian, Danmei,Wang, Fangfang,Xu, Zhipeng,Zhang, Meng,Zhang, Youwei
-
-
- Cinnamyl-containing rupestonic acid methyl ester derivative as well as preparation method and application of rupestonic acid methyl ester derivative
-
The invention relates to a cinnamyl-containing rupestonic acid methyl ester derivative as well as a preparation method and application thereof, the derivative is prepared by the following steps: reacting rupestonic acid with dimethyl sulfate to obtain rupestonic acid methyl ester, and then obtaining 2-hydroxyl rupestonic acid methyl ester under the oxidation of camphor sulfonyl acridine. and then reacting with cinnamyl chloride under the catalysis of DMAP to obtain 20 rupestonic acid methyl ester derivatives containing cinnamyl groups. The method has the advantages of mild reaction conditions and simple experimental steps. The obtained 1d-20d rupestonic acid methyl ester derivatives containing the cinnamyl groups are subjected to a preliminary in-vitro anti-influenza A H3N2 virus activity test. Experimental results show that the compounds show good activity in 7d, 15d and 18d, and can be used as drugs for resisting influenza A H3N2 virus.
- -
-
Paragraph 0147-0148; 0151
(2021/06/02)
-
- Meta-substituted piperlongumine derivatives attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis
-
Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta-substituent containing derivatives 1–3 and 1–6, in which γ-butyrolactam replaced α,β-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta-substituted derivative, compared with the corresponding ortho- or para-substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1–3 and 1–6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1–3 or 1–6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta-substituted derivatives 1–3 and 1–6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
- Gong, Zhaotang,Liu, Guoyun,Mu, Wenwen,Wang, Ziqing,Yang, Jie
-
-
- Practical access to fluorescent 2,3-naphthalimide derivatives: Via didehydro-Diels-Alder reaction
-
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.
- 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)
-
- The potential role of the 5,6-dihydropyridin-2(1: H)-one unit of piperlongumine on the anticancer activity
-
Piperlongumine (PL), a potent anticancer agent from the plant long pepper (Piper longum), contains the 5,6-dihydropyridin-2(1H)-one heterocyclic scaffold and cinnamoyl unit. In this paper, we synthesized a series of PL analogs and evaluated their cytotoxicity against cancer cells for the sake of exploring which pharmacophore plays a more potent role in enhancing the anticancer activities of PL. These results illustrated that the position effect, not the electronic effect, of substituents plays a certain role in the cytotoxicity of PL and its analogs. More important, the 5,6-dihydropyridin-2(1H)-one unit, a potent pharmacophore in enhancing the antiproliferative activities of PL, could react with cysteamine and lead to ROS generation, and then bring about the occurrence of ROS-induced downstream events, followed by cell cycle arrest and apoptosis. This work suggests that introducing a lactam unit containing Michael acceptors may be a potent strategy to enhancing the anticancer activity of drugs. This journal is
- Li, Peng-Xiao,Liu, Guo-Yun,Liu, Yue,Mu, Wen-Wen,Yang, Jie
-
p. 42128 - 42136
(2020/12/09)
-
- New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation
-
Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, hCA II, hCA IX and hCA XII for their inhibitory action. All new compounds when screened for carbonic anhydrase inhibitory activity have shown selective inhibition towards the tumor associated isoforms hCA IX and XII over CA I and II, with inhibition constants in the submicromolar to low nanomolar range. Compound 6b and 14g exhibited significant inhibition with low nanomolar potency against hCA IX, whereas 6k was effective against hCA XII. Compounds 6b, 14g and 6k may be considered as lead molecules for future development of cancer therapeutics based on a novel mechanism of action.
- Angeli, Andrea,Arifuddin, Mohammed,Singh, Priti,Supuran, Claudiu T.,Swain, Baijayantimala
-
-
- Structure based modification of chalcone analogue activates Nrf2 in the human retinal pigment epithelial cell line ARPE-19
-
Oxidative stress-induced degeneration of retinal pigment epithelial (RPE) cells is known to be a key contributor to the development of age-related macular degeneration (AMD). Activation of the nuclear factor-(erythroid-derived 2)-related factor-2 (Nrf2)-mediated cellular defense system is believed to be a valid therapeutic approach. In the present study, we designed and synthesized a novel chalcone analogue, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), as a Nrf2 activator. The potency of Tak was measured in RPE cells by the induction of the Nrf2-dependent antioxidant genes HO-1, NQO-1, GCLc, and GCLm, which were regulated through the Erk pathway. We also showed that Tak could protect RPE cells against oxidative stress-induced cell death and mitochondrial dysfunction. Furthermore, by modifying the α, β unsaturated carbonyl entity in Tak, we showed that the induction of antioxidant genes was abolished, indicating that this unique feature in Tak was responsible for the Nrf2 activation. These results suggest that Tak is a potential candidate for clinical application against AMD.
- Cao, Ruijun,Cui, Yuting,Feng, Zhihui,Huang, Na,Li, Yuan,Liu, Jiankang,Meng, Lingjie,Xiong, Yue
-
-
- Novel paeonol derivatives: Design, synthesis and anti-inflammatory activity in vitro and in vivo
-
Paeonol has been proved to have potential anti-inflammatory activity, but its clinical application is not extensive due to the poor anti-inflammatory activity (14.74% inhibitory activity at 20 μM). In order to discover novel lead compound with high anti-inflammatory activity, series of paeonol derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. Structure-activity relationships (SARs) have been fully concluded, and finally (E)-N-(4-(2-acetyl-5-methoxyphenoxy)phenyl)-3-(3,4,5-trimet-hoxyphenyl)acrylamide (compound 11a) was found to be the best active compound with low toxicity, which showed 96.32% inhibitory activity at 20 μM and IC50 value of 6.96 μM against LPS-induced over expression of nitric oxide (NO) in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4, resulting in inhibiting of NF-κB and MAPK pathways. Further studies have shown that compound 11a has obvious therapeutic effect against the adjuvant-induced rat arthritis model.
- Hu, Yang Sheng,Han, Xu,Yu, Pei Jing,Jiao, Ming Ming,Liu, Xin Hua,Shi, Jing Bo
-
-
- Design, synthesis and biological evaluation of novel carboline-cinnamic acid hybrids as multifunctional agents for treatment of Alzheimer's disease
-
Alzheimer's disease (AD) is a complex neurodegenerative disease with multiple pathological features. Multifunctional compounds able to simultaneously interact with several pathological components have been considered as a solution to treat the complex pathologies of neurodegenerative diseases. β-carboline and cinnamic acid have been extensively studied for their widespread biological effects in treatment of AD, further application is limited due to its poor solubility and high toxicity. Herein, a series of carboline-cinnamic acid hybrids was designed and synthesized to obtain new multifunctional molecules with low toxicity and good physicochemical properties. In particular, e3 and e12 exhibited significant inhibition of Aβ aggregation (inhibitory rate at 25 μM: 65% and 72% respectively), moderate BuChE inhibition, excellent neuroprotective effects and low neurotoxicity. Furthermore, in the AD mice model, e3 and e12 could restore learning and memory function to a comparable level to that of the control and did not exhibit any acute toxicity in vivo at a relatively high dose of 600 mg/kg. Thus, these new compounds can be further studied as multifunctional molecules for AD.
- Feng, Feng,Jiang, Pan,Li, Qi,Liao, Qinghong,Liu, Wenyuan,Qu, Wei,Sun, Haopeng,Yan, Yuhui,Zhao, Yifan
-
-
- Design and synthesis novel di-carbonyl analogs of curcumin (DACs) act as potent anti-inflammatory agents against LPS-induced acute lung injury (ALI)
-
A novel series of di-carbonyl analogs of curcumin (DACs) were prepared and evaluated for their anti-inflammatory properties. Preliminary results showed that a vast majority of compounds tested in this study could effectively suppress LPS-induced production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Structure-activity relationships of the compounds were discussed. Compounds 5a27 and 5a28 showed the most potent anti-inflammatory activities and had higher structural stability and orally bioavailability than curcumin in vitro. Mechanistically, they inhibited the activation of macrophages via the blockade of mitogen-activated protein kinase (MAPK) signaling and nuclear translocation of NF-κB. In vivo, 5a27 and 5a28 markedly alleviated lipopolysaccharides (LPS)-induced acute lung injury (ALI). The wet/dry ratio of lungs was significantly normalized by the active compounds, which was consistent with the suppression of neutrophil infiltration and production of proinflammatory cytokines. Collectively, these results present a new series of curcumin analogs as promising anti-inflammatory agents for treatment of ALI.
- Qian, Jianchang,Chen, Xianxin,Shu, Sheng,Zhang, Wenxin,Fang, Bo,Chen, Xiaojing,Zhao, Yunjie,Liu, Zhiguo,Liang, Guang
-
p. 414 - 425
(2019/02/19)
-
- Preparation and anti-tumor activity of piplartine derivative
-
The invention discloses a biological structural formula of a piplartine derivative. The compound is of a novel structure. The invention further discloses a preparation method and use of the compound.The compound has obvious inhibition effects to the tumor cells of pancreatic cancer, cervical cancer, colon cancer, malignant melanoma, lung adenocarcinoma, leukemia, ovarian cancer and the like. Thestructural formula of the compound is formula (shown in the description).
- -
-
Paragraph 0007; 0008
(2019/04/13)
-
- Activity-based protein profiling reveals GSTO1 as the covalent target of piperlongumine and a promising target for combination therapy for cancer
-
Through systematic target identification for piperlongumine, a cancer-selective killing molecule, we identified GSTO1 as its major covalent target for cancer cell death induction. We also reveal that GSTO1 inhibition is a promising combination strategy with other anti-cancer agents by drug combination screening in which piperlongumine exhibits broad-spectrum synergistic effects with a large proportion of the tested anti-cancer agents, especially with PI3K/Akt/mTOR pathway inhibitors.
- Li, Li,Zhao, Yue,Cao, Ran,Li, Lin,Cai, Gaihong,Li, Jiaojiao,Qi, Xiangbing,Chen, She,Zhang, Zhiyuan
-
supporting information
p. 4407 - 4410
(2019/04/26)
-
- Synthesis of Dicarbonyl Curcumin Analogues Containing the Tropane Scaffold
-
A general synthetic route to the unknown 1,3-dicarbonyl tropane derived curcumin analogues was developed. The method was based on the aldol condensation reaction (40–90 % yield, two steps without product isolation) and acylation of the resulting 2-benzylidenetropinones with substituted cinnamoyl cyanides (yields 41–91 %). Overall 18 new tropane derivatives featuring the characteristic curcuminoid hepta-1,6-dien-3,5-dione structure were synthesized and characterized. The range of the substituted aromatic rings in the prepared analogues included Ph, m-MeO-C6H4, 3,4-di-MeO-C6H3, 3,4,5-tri-MeO-C6H2, p-Br-C6H4, p-F-C6H4, p-CF3-C6H4, p-NO2-C6H4, 2-NO2-4,5-di-CH3O-C6H2, 2-NO2-4,5-O-CH2-O-C6H2, 3-MeO-4-[CH(CH3)-OEt]-C6H3, 3-MeO-4-OH-C6H3, p-MeO-C6H4, 4,5-O-CH2-O-C6H3, 3-MeO-4-MeOCOO. Two orthogonal protective groups for hydroxyl (acetal or carbonate), removable in acidic or basic conditions, were used for synthesizing curcuminoids with free phenolic groups (3-MeO-4-OH-C6H3).
- Wolosewicz, Karol,Podgorska, Katarzyna,Rutkowska, Ewelina,Lazny, Ryszard
-
p. 4662 - 4674
(2019/08/01)
-
- Synthesis and biological evaluation of celastrol derivatives as anti-ovarian cancer stem cell agents
-
Ovarian cancer is associated with a high percentage of recurrence of tumors and resistance to chemotherapy. Cancer stem cells (CSCs) are responsible for cancer progression, tumor recurrence, metastasis, and chemoresistance. Thus, developing CSC-targeting therapy is an urgent need in cancer research and clinical application. In an attempt to achieve potent and selective anti-CSC agents, a series of celastrol derivatives with cinnamamide chains were synthesized and evaluated for their anti-ovarian cancer activities. Most of the compounds exhibited stronger antiproliferative activity than celastrol, and celastrol derivative 7g with a 3,4,5-trimethoxycinnamamide side chain was found to be the most potent antiproliferative agent against ovarian cancer cells with an IC50 value of 0.6 μM. Additionally, compound 7g significantly inhibited the colony formation ability and reduced the number of tumor spheres. Furthermore, compound 7g decreased the percentage of CD44+, CD133+ and ALDH+ cells. Thus, compound 7g is a promising anti-CSC agent and could serve as a candidate for the development of new anti-ovarian cancer drugs.
- Li, Xiaojing,Ding, Jie,Li, Ning,Liu, Wenxia,Ding,Zheng, Huijuan,Ning, Yanyan,Wang, Hongmin,Liu, Renmin,Ren, Shaoda
-
p. 667 - 679
(2019/07/05)
-
- Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors
-
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer’s disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 ± 0.91 μM) which was stronger than neostigmine (12.01 ± 0.45 μM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer’s disease.
- Gao, Cheng-Zhi,Dong, Wei,Cui, Zhi-Wen,Yuan, Qiong,Hu, Xia-Min,Wu, Qing-Ming,Han, Xianlin,Xu, Yao,Min, Zhen-Li
-
p. 150 - 162
(2018/11/30)
-
- Pyridazinone derivative, and preparation method and medical application thereof
-
The invention provides a pyridazinone derivative, and a preparation method and a medical application thereof. O-formylbenzoic acid used as a raw material reacts with dimethyl phosphite to obtain dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate, the dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate reacts with 3-cyano-4-fluorobenzaldehyde in the presence of triethylamine to prepare (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile, and the (Z,E)-2-fluoro-5-[(3-oxoisobenzofuran-1(3H)-ylidene)methyl]benzonitrile is reduced by hydrazine hydrate to prepare 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid; and benzaldehyde or substituted aromatic formaldehyde or furfural used as a raw material and malonic acid undergo a Knoevenagel reaction to obtain cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid, the cinnamic acid or substituted cinnamic acid or furan-2-acrylic acid and 1-tert-butoxycarbonylpiperazine undergo an amidation reaction, a tert-butoxycarbonyl group is removed from the obtained amidation product in the presence of trifluoroacetic acid, and the obtained product and the 2-fluoro-5-[(4-oxo-3,4-dihydropyridazin-1-yl)methyl]benzoic acid undergo the amidation reaction to obtain a series of (E)-4-{3-[4-[(3-substituted aryl)acryloyl]piperazin-1-carbonyl]-4-fluorobenzyl}-2H-pyridazin-1-one derivatives. Results of preliminary pharmacological activity screening show that the compound represented by a general formula shown in the present invention has a certain in-vitro PARP-1 inhibition ability and a certain in-vitro tumor cell proliferation resisting activity. The structural general formula of compound is shown in the description; and in the general formula, Ar is selected from two formulas also shown in the description, and R1, R2, R3, R3, R4 and R5 can be the hydrogen atom, the fluorine atom, the chlorine atom, the bromine atom, a methyl group, a methoxy group, a tetrafluoromethyl group and a nitro group.
- -
-
-
- Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification
-
A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.
- Huy, Peter H.,Mbouhom, Christelle
-
p. 7399 - 7406
(2019/08/20)
-
- Synthesis and discovery of 18β-glycyrrhetinic acid derivatives inhibiting cancer stem cell properties in ovarian cancer cells
-
Despite advances in ovarian cancer treatment, the five-year overall survival rate is less than 30% with the presence of cancer stem cells (CSCs). To develop CSC-targeting therapy, a series of 18β-glycyrrhetinic acid (GA) derivatives containing cinnamamide moiety have been designed, synthesized, and screened for their antiproliferative activity in SKOV3 and OVCAR3 cells. Most of the compounds exhibited stronger antiproliferative activity than GA, and compound 7c was the most active one. Further biological studies showed that compound 7c could induce apoptosis and suppress migration. In addition, compound 7c could not only observably decrease the colony formation and sphere formation ability, but also significantly reduce the CD44+, CD133+, and ALDH+ subpopulation in SKOV3 and OVCAR3 cells. In conclusion, these results indicate that compound 7c is a promising anti-CSC agent for further anti-ovarian cancer studies.
- Li, Xiaojing,Liu, Yihua,Wang, Na,Liu, Yuyu,Wang, Shuai,Wang, Hongmin,Li, Aihua,Ren, Shaoda
-
p. 27294 - 27304
(2019/09/12)
-
- Method for preparing hydroxyl-2(1H)-quinolinone
-
The invention discloses a method for preparing hydroxyl-2(1H)-quinolinone, and belongs to the field of organic chemistry. The method comprises the following steps: enabling an aminophenylboric acid compound and trans-beta-aryl acryloyl chloride to react under the existence of triethylamine or pyridine so as to generate a trans-amide intermediate, and then carrying out temperature rising reaction in an organic solvent under the existence of aluminum chloride anhydrous and B(C6F5)3; cooling after completing the reaction, and adding hydrogen peroxide for oxidization, thus obtaining the hydroxyl-2(1H)-quinolinone. The method disclosed by the invention has the advantages that raw materials are easy to obtain, hydroxyl quinolinone products in different positions can be obtained through differentinitial raw materials, and an existing synthetic route is enriched.
- -
-
Paragraph 0059; 0060; 0061; 0062
(2018/03/28)
-
- Synthesis of a series of benzothiazole amide derivatives and their biological evaluation as potent hemostatic agents
-
A series of benzothiazole amide derivatives were synthesized through a facile and efficient method via a nucleophilic acyl substitution reaction between 2-aminobenzothiazole and various cinnamic acid compounds. The obtained products exhibited good thermal stabilities. All compounds were evaluated for their in vitro hemostatic activities using the commercially available standard drug etamsylate as a positive control. The results showed that compound Q2 had a significant partial coagulation activity, reduced capillary permeability at 5, 10 and 50 μmol L-1, activated thrombin activity, and a more potent platelet aggregation activity than the positive control group (etamsylate, up to 1283.9 times in the nanomole range). A molecular modeling study revealed that compound Q2 was a competitive thrombin activator. Therefore, Q2 may be a potential lead for further biological screening and for the generation of drug molecules. Moreover, the structure-activity relationship of the prepared compounds is also discussed herein.
- Nong, Wenqian,Zhao, Anran,Wei, Jinrui,Cheng, Hui,Luo, Xuan,Lin, Cuiwu
-
p. 6231 - 6241
(2018/02/19)
-
- Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation
-
Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.
- Liu, Xingui,Wang, Yingying,Zhang, Xuan,Gao, Zhengya,Zhang, Suping,Shi, Peizhong,Zhang, Xin,Song, Lin,Hendrickson, Howard,Zhou, Daohong,Zheng, Guangrong
-
p. 3925 - 3938
(2018/06/19)
-
- Styrylpyrazolopyrimidine compound, medicinal composition and preparation method and application
-
The invention provides a styrylpyrazolopyrimidine compound. The structure of the styrylpyrazolopyrimidine compound is shown as a structural formula I, wherein in the structural formula I, each of R1 and R2 is one selected from H, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl AND piperazinyl or substituted piperazinyl; each of R', R', R'' and R'' isone selected from H, halogen, C1-C5 alkyl, nitro, C1-C3 alkoxy, C1-C3 alkylamino, hydroxy, acetamido and trifluoromethyl. The invention further provides a preparation method of the styrylpyrazolopyrimidine compound, a medicinal composition using the styrylpyrazolopyrimidine compound as an active compound and the application thereof. The styrylpyrazolopyrimidine compound has the advantages as follows: the styrylpyrazolopyrimidine compound has good anti-inflammatory activity and shows a good application prospect in treatment of various acute and chronic inflammations.
- -
-
Paragraph 0065; 0067; 0069
(2018/10/04)
-
- Stereocontrolled Synthesis of trans/ cis-2,3-Disubstituted Cyclopropane-1,1-diesters and Applications in the Syntheses of Furanolignans
-
A new Michael addition/intramolecular alkylation sequence of (Z)-3-(2-bromo-3-arylacryloyl)oxazolidin-2-ones and malonates was developed. By a simple switch of the reaction conditions including the base promoter, solvent, and reaction temperature, both of the cis- and trans-isomers of a series of oxazolidinone-containing 2,3-disubstituted cyclopropane-1,1-diesters could be obtained in good-to-excellent yields and with an excellent diastereoselectivity. The utility of the cyclopropane products was demonstrated in the diastereoselective syntheses of (±)-urinaligran and a stereoisomer of (±)-virgatusin involving the AlCl3-promoted [3+2] annulation with veraldehyde or piperonal as the key step.
- Shen, Yue,Chai, Jun,Yang, Gaosheng,Chen, Wenlong,Chai, Zhuo
-
supporting information
p. 12549 - 12558
(2018/10/09)
-
- Fragmentation pattern of amides by EI and HRESI: Study of protonation sites using DFT-3LYP data
-
Amides are important natural products which occur in a few plant families. Piplartine and piperine, major amides in Piper tuberculatum and P. nigrum, respectively, have shown a typical N-CO cleavage when analyzed by EI-MS or HRESI-MS. In this study several synthetic analogs of piplartine and piperine were subjected to both types of mass spectrometric analysis in order to identify structural features influencing fragmentation. Most of the amides showed an intense signal of the protonated molecule [M + H]+ when subjected to both HRESI-MS and EI-MS conditions, with a common outcome being the cleavage of the amide bond (N-CO). This results in the loss of the neutral amine or lactam and the formation of aryl acylium cations. The mechanism of N-CO bond cleavage persists in α,β-unsaturated amides because of the stability caused by extended conjugation. Computational methods determined that the protonation of the piperamides and their derivatives takes place preferentially at the amide nitrogen supporting the dominant the N-CO bond cleavage.
- Fokoue,Marques,Correia,Yamaguchi,Qu,Aires-De-Sousa,Scotti,Lopes,Kato
-
p. 21407 - 21413
(2018/06/26)
-
- Design, synthesis, bioactivity, and computational studies of some morpholine-clubbed coumarinyl acetamide and cinnamide derivatives
-
Abstract: The novel derivatives of morpholine-clubbed 3-substituted coumarinyl acetamide and cinnamide derivatives 5a–5j and 6a–6j have been synthesized via various 2-chloro-N-phenyl acetamide and cinnamoyl chloride derivatives, respectively. The required motif has been generated through Vilsmeier–Haack reaction on 4-hydroxycoumarin annelation of morpholine followed by imine formation and subsequently condensation with various 2-chloro-N-phenylacetamide and cinnamoyl chloride to furnish the desired molecule. The synthesized molecules were characterized by various spectroscopic methods viz IR, 1H NMR, 13C NMR. Their antimicrobial activities against various strains of bacteria and fungi have been evaluated, and computational studies have also been performed for all the newly synthesized analogs. Graphical Abstract: [Figure not available: see fulltext.].
- Chauhan, Prakashsingh M.,Thummar, Sandeep N.,Chikhalia, Kishor H.
-
p. 1261 - 1277
(2018/05/22)
-
- Synthesis of coumarin derivatives and their cytoprotective effects on t-BHP-induced oxidative damage in HepG2 cells
-
Coumarins are ubiquitous in higher plants and exhibit various biological actions. The aim of this study was to investigate the structure-activity relationships of coumarin derivatives on tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human hepatoma HepG2 cells. A series of coumarin derivatives were prepared and assessed for their cytoprotective effects. Among these, a caffeoyl acid-conjugated dihydropyranocoumarin derivative, caffeoyllomatin, efficiently protected against cell damage elicited by t-BHP. Our findings suggest that caffeoyllomatin appears to be a potent cytoprotective agent.
- Ando, Tomomi,Nagumo, Mina,Ninomiya, Masayuki,Tanaka, Kaori,Linhardt, Robert J.,Koketsu, Mamoru
-
supporting information
p. 2422 - 2425
(2018/06/20)
-
- Synthesis of piplartine analogs and preliminary findings on structure–antimicrobial activity relationship
-
In this work it is described the synthesis, characterization and antimicrobial and toxicity evaluation of a series of analogs of piplartine, a piperamide found in Piper sp. The compounds structures were confirmed by infrared spectroscopy, 1H, 13C nuclear magnetic resonance, high resolution mass spectroscopy and were evaluated against strains of Candida spp., Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Derivative 24 was almost four-fold more potent (IC50: 48.83 μM) and five-fold less toxic (SI > 3) than piplartine (IC50: 189.2 μM; SI: 0.21) against Candida krusei, as well as two-fold more potent than fluconazole (IC50: 104.48 μM). This compound was also active against Candida tropicalis at 97.67 μM. Benzoyl derivative 17 was three-fold more potent (IC50: 85.2 μM) and more than five-fold less toxic (CC50: 231.71 μM) than piplartine (IC50: 315.33 μM and CC50: 41.14 μM) against Staphylococcus aureus. Given these findings, we have found analogs of piplartine which can be assumed as prototypes for the optimization and the development of new antimicrobial (compounds 24 and 17) agents.
- Fregnan, Antonio Maciel,Brancaglion, Guilherme Andrade,Galv?o, Alexandre Francisco Cerqueira,D’Sousa Costa, Cinara Oliveira,Moreira, Diogo Rodrigo Magalh?es,Soares, Milena Botelho Pereira,Bezerra, Daniel Pereira,Silva, Naiara Chaves,de Souza Morais, Stella Maria,Oliver, Josidel Concei??o,Dias, Amanda Latercia Tranches,Coelho, Luiz Felipe Leomil,Carvalho, Diogo Teixeira,Dias, Danielle Ferreira,de Souza, Thiago Belarmino
-
p. 603 - 614
(2017/02/15)
-
- Synthesis and in?vitro and in?vivo antitumour activity study of 11-hydroxyl esterified bergenin/cinnamic acid hybrids
-
Fourteen bergenin/cinnamic acid hybrids were synthesized, characterized and evaluated for their antitumour activity both in?vitro and in?vivo. The most potent compound, 5c, arrested HepG2 cells (IC50?=?4.23?±?0.79?μM) in the G2/M phase and induced cellular apoptosis. Moreover, compound 5c was also found to suppress the tumour growth in Heps xenograft-bearing mice with low toxicity. In the mechanistic study, 5c administration ignited a mitochondria-mediated apoptosis pathway of HepG2 cell death. Furthermore, 5c activated Akt-dependent pathways and further decreased the expression of the Bcl-2 family of proteins. The downstream mitochondrial p53 translocation was also significantly activated, accompanied by an increase of the caspase-9, caspase-3 activation. These data imply that bergenin/cinnamic acid hybrids could serve as novel Akt/Bcl-2 inhibitors for further preclinical studies.
- Liang, Chengyuan,Pei, Shaomeng,Ju, Weihui,Jia, Minyi,Tian, Danni,Tang, Yonghong,Mao, Gennian
-
p. 319 - 328
(2017/04/11)
-
- Structure–Activity Relationship Studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Multidrug Resistance Reversers
-
A series of derivatives were synthesized and studied with the aim to investigate the structure–activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar. Then, different aryl-substituted amides were inserted, and to explore the effects of varying the amide function, the corresponding isosteric ester derivatives and some alkylamine analogues were synthesized. The new compounds were studied to evaluate their P-gp interaction profile and selectivity toward the two other ABC transporters, multidrug-resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP). Investigation of the chemical stability of the amide and ester derivatives toward spontaneous or enzymatic hydrolysis showed that these compounds were stable in phosphate-buffered saline and human plasma. This study allowed us to evaluate the selectivity of the three series on the three efflux pumps and to propose the structural requirements that define the P-gp interaction profile. We identified two P-gp substrates, a P-gp inhibitor, and three ester derivatives that were active on BCRP, which opens a new scenario in the development of ligands active toward this pump.
- Teodori, Elisabetta,Dei, Silvia,Bartolucci, Gianluca,Perrone, Maria Grazia,Manetti, Dina,Romanelli, Maria Novella,Contino, Marialessandra,Colabufo, Nicola Antonio
-
p. 1369 - 1379
(2017/09/01)
-
- Synthesis and biological evaluation of a new series of cinnamic acid amide derivatives as potent haemostatic agents containing a 2-aminothiazole substructure
-
Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC50 = 1.87 μmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC50 = 46.22 μmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study.
- Nong, Wenqian,Zhao, Anran,Wei, Jinrui,Lin, Xiao,Wang, Lisheng,Lin, Cuiwu
-
supporting information
p. 4506 - 4511
(2017/09/12)
-
- Long pepper amide analogs, preparation method and application thereof
-
The invention relates to the pharmaceutical chemistry field, and concretely relates to a piplartine analogue (I) or (II), a preparation method therefor and pharmaceutical compositions containing the piplartine analogue (I) and (II). The pharmacodynamic experiments prove that piplartine analogue can be used for treating or preventing thromboembolism diseases. The structural formulas of the piplartine analogue (I) and (II) are shown in the specification.
- -
-
Paragraph 0035; 0036
(2017/08/25)
-
- Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine amide-cinnamamide hybrids
-
We report herein the design and synthesis of a series of novel imidazo[1,2- A]pyridine amide-cinnamamide hybrids linked via an alkyl carbon chain. All 38 new hybrids were evaluated for their antimycobacterial activity against M. tuberculosis (MTB) H37Rv ATCC 27294 using the microplate Alamar Blue assay (MABA). Although the hybrids are less active than the two reference compounds, the promising activity (MICs: 4 μg/mL) of 2,6-dimethylimidazo[1,2-a]pyridine amide-cinnamamide hybrids 11e and 11k could be a good starting point to further find new lead compounds against multi-drug-resistant tuberculosis.
- Li, Linhu,Li, Zhuorong,Liu, Mingliang,Shen, Weiyi,Wang, Bin,Guo, Huiyuan,Lu, Yu
-
-
- Pipelongumine and its derivatives and producing method thereof
-
The present invention relates to piperlongumine, a derivative thereof, and a synthesizing method thereof. The piperlongumine and the derivatives thereof are synthesized by making a variety of amides/lactams react with a variety of acid chlorides of 3,4,5-trimethoxycinnamic acid. In addition, anti-inflammatory effect is tested in RAW264.7 macrophage induced by LPS with respect to the compounds. The piperlongumine of the compounds shows maximum inhibition activity (91.3%) and has cytotoxicity. A compound 3 having alpha, beta-unsaturated butyrolactam does not show cytotoxicity, and has a significant inhibition effect of 64.8%. An amide/lactam region connected to an alpha, beta-unsaturated cinnamoyl group having the chain length of at least three carbons exhibits a strong anti-inflammatory activity without cytotoxicity.
- -
-
Page/Page column 14
(2017/01/05)
-