- Design, synthesis, biological evaluation and silico prediction of novel sinomenine derivatives
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Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty‐three compounds were synthesized and characterized by spectroscopy (IR,1H‐NMR,13C‐NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF‐7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine‐containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer‐related core targets and verified their interaction with derivatives through molecular docking. The chlorine‐containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine‐containing derivatives might be a promising lead for the development of new anticancer agents.
- Cui, Dongmei,Gao, Mingjie,Li, Jinjie,Li, Shoujie,Nian, Xin,Zhang, Chen,Zhang, Liyu,Zhao, Changqi
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- Design, synthesis and biological evaluation of novel pyrrolidone-based derivatives as potent p53-MDM2 inhibitors
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Inhibition of the interactions of the tumor suppressor protein p53 with its negative regulators MDM2 in vitro and in vivo, representing a valuable therapeutic strategy for cancer treatment. The natural product chalcone exhibited moderate inhibitory activity against MDM2, thus based on the binding mode between chalcone and MDM2, a hit unsaturated pyrrolidone scaffold was obtained through virtual screening. Several unsaturated pyrrolidone derivatives were synthesized and biological evaluated. As a result, because the three critical hydrophobic pockets of MDM2 were occupied by the substituted-phenyl linked at the pyrrolidone fragment, compound 4 h demonstrated good binding affinity with the MDM2. Additionally, compound 4 h also showed excellent antitumor activity and selectivity, and no cytotoxicity against normal cells in vitro. The further antitumor mechanism studies were indicated that compound 4 h could successfully induce the activation of p53 and corresponding downstream p21 proteins, thus successfully causing HCT116 cell cycle arrest in the G1/M phase and apoptosis. Thus, the novel unsaturated pyrrolidone p53-MDM2 inhibitors could be developed as novel antitumor agents.
- Si, Dongjuan,Luo, Huijuan,Zhang, Xiaomeng,Yang, Kundi,Wen, Hongmei,Li, Wei,Liu, Jian
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- Quantitative activity-activity relationship (QAAR) driven design to develop hydroxamate derivatives of pentanoic acids as selective HDAC8 inhibitors: synthesis, biological evaluation and binding mode of interaction studies
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Histone deacetylase 8 (HDAC8) has been implicated as a potential drug target of many diseases including cancer. HDAC8 isoform selectivity over other class-I HDACs is a major concern nowadays. In this work, a series of pentanoic acid based hydroxamates wit
- Adhikari, Nilanjan,Amin, Sk. Abdul,Das, Sanjib,Ghosh, Balaram,Jha, Tarun,Routholla, Ganesh,Trivedi, Prakruti,Vijayasarathi, Dhanya
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p. 17149 - 17162
(2021/10/04)
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- N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
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A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 μM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10?3 s?1) from the catalytic domain.
- Fang, Hai-Lian,He, Jie-Ling,Li, Wei-Yi,Liu, Shan-Shan,Ni, Wei-Wei,Pan, Xing-Ming,Xiao, Zhu-Ping,Ye, Ya-Xi,Yi, Juan,Zhou, Mi,Zhou, Tian-Li,Zhu, Hai-Liang
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p. 404 - 413
(2020/01/03)
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- Phosphonic acid analogs of fluorophenylalanines as inhibitors of human and porcine aminopeptidases N: Validation of the importance of the substitution of the aromatic ring
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A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.
- Dziuk, B?a?ej,Kafarski, Pawe?,Pirat, Jean-Luc,Talma, Micha?,Wanat, Weronika
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- FUSED [1,2,4]THIADIAZINE DERIVATIVES WHICH ACT AS KAT INHIBITORS OF THE MYST FAMILY
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A compound of formula (I): which inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HBO1 and MOF.
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Page/Page column 236
(2019/03/17)
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- Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space
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A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.
- Tajabadi, Fatemeh Mazraati,Pouwer, Rebecca H.,Liu, Miaomiao,Dashti, Yousef,Campitelli, Marc R.,Murtaza, Mariyam,Mellick, George D.,Wood, Stephen A.,Jenkins, Ian D.,Quinn, Ronald J.
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p. 6609 - 6628
(2018/07/25)
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- SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS NADPH OXIDASE INHIBITORS
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The present application relates to substituted fused heteroaryl and heterocyclic compounds, useful as nicotinamide adenine dinucleotide phosphate oxidase inhibitors (NADPH oxidase inhibitors), processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by NADPH oxidase. (Formula I)
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Page/Page column 104-105
(2018/12/03)
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- Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors
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In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed.
- Peng, Cheng-Kang,Zeng, Ting,Xu, Xing-Jun,Chang, Yi-Qun,Hou, Wen,Lu, Kuo,Lin, Hui,Sun, Ping-Hua,Lin, Jing,Chen, Wei-Min
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p. 187 - 199
(2017/01/06)
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- Novel triazole derivative with anti-inflammatory and anti-hyperglycemic activity and method for preparing the same
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The present invention relates to a novel triazole derivative having anti-inflammatory and anti-diabetic activities, to a production method thereof, and to a pharmaceutical composition for preventing or treating inflammatory diseases and diabetic diseases, comprising the same. The novel triazole derivative according to the present invention has excellent inhibitory activity of type II collagen and COX-2 and exhibits anti-inflammatory activity, and thus can be used as a pharmaceutical composition for the preventing or treating inflammatory diseases. In addition, anti-diabetic activity is showed due to excellent inhibitory activities of alpha-glucosidase and alpha-amylase, thereby being able to be used as a pharmaceutical composition for preventing or treating diabetes diseases.COPYRIGHT KIPO 2017
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Paragraph 0074; 0075
(2017/08/23)
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- Stereoselective synthesis of Z-vinylsilanes via palladium-catalyzed direct intermolecular silylation of C(sp2)-H bonds
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An efficient and convenient palladium-catalyzed direct intermolecular silylation of C(sp2)-H bonds by using disilanes as the silicon source with the assistance of a readily removable bidentate directing group is reported. This strategy provided a regio- and stereoselective protocol for exclusive synthesis of Z-vinylsilanes with reasonable to excellent yields and good functional group compatibility. Silylation of the isolated palladacycle intermediate revealed the Z-stereoselective pathway. Moreover, the practicality and effectiveness of this method were illustrated by a gram-scale experiment and further functionalization of the silylation product.
- Pan, Jin-Long,Chen, Chao,Ma, Zhi-Gang,Zhou, Jia,Wang, Li-Ren,Zhang, Shu-Yu
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supporting information
p. 5216 - 5219
(2017/11/06)
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- Synthesis, structural elucidation and bioevaluation of 4-amino-1,2,4-triazole-3-thione's Schiff base derivatives
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In this study, a series of ten triazole Schiff base derivatives 6a-j were synthesized through microwave assisted imine formation by reacting substituted amino triazole 5 with different substituted aldehydes. All the synthesized compounds were evaluated fo
- Rafiq, Muhammad,Saleem, Muhammad,Hanif, Muhammad,Kang, Sung Kwon,Seo, Sung-Yum,Lee, Ki Hwan
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p. 161 - 171
(2016/03/12)
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- Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity
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Recent analyses have highlighted the promotion of cancer migration and invasion, mediated through HDAC via MMP-2 and MMP-9. Since both class 1 HDACs and MMP-2/9 are involved in the migration and invasion of cancer, an attempt has been taken to design dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping and molecular docking approaches. The designed molecules were synthesized and showed a range of inhibitory activity against different MMP subtypes. Most of these designed compounds were selective towards MMP-2 but less potent against anti-targets like MMP-8, -12, etc. The highly active MMP-2 inhibitors were also found to be active towards HDAC-8 but less potent against other class 1 HDACs (HDAC-1 and -2). Molecular dynamics simulations revealed that the designed compounds may be acting through a distinct mechanism of action in the 'acetate ion channel' of HDAC-8. Some potent dual MMP-2/HDAC-8 inhibitors were further explored for in vitro cellular assays against human lung carcinoma cell line A549. These analyses revealed that some of these dual inhibitors have considerable anti-migratory and anti-invasive properties. The work may help to obtain some useful dual inhibitors.
- Halder, Amit K.,Mallick, Sumana,Shikha, Deep,Saha, Achintya,Saha, Krishna D.,Jha, Tarun
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p. 72373 - 72386
(2015/09/08)
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- Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors
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A series of 4-arylamido 3-methyl isoxazoles were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Most compounds showed selective antiproliferative activity toward the U937 cell line and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide 5a-b, 6a-o and urea 7a-n, 8a-g with hydrophobic moieties, and one of the most potent inhibitor 6a, 5-methyl-N-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-4-carboxamide was found to be very potent inhibitor of FMS kinase (GI50 Combining double low line 0.016 μM, IC50 Combining double low line 9.95 nM) with excellent selectivity profiles and is a promising candidate for further development in therapeutics for cancer.
- Im, Daseul,Jung, Kyungjin,Yang, Songyi,Aman, Waqar,Hah, Jung-Mi
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p. 600 - 610
(2015/09/08)
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- Ligand-Enabled Meta-C-H Alkylation and Arylation Using a Modified Norbornene
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2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd(II)-catalyzed meta-C(sp2)-H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed.
- Shen, Peng-Xiang,Wang, Xiao-Chen,Wang, Peng,Zhu, Ru-Yi,Yu, Jin-Quan
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supporting information
p. 11574 - 11577
(2015/09/28)
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- Syn/anti switching by specific heteroatom-titanium coordination in the Mannich-like synthesis of 2,3-diaryl-β-amino acid derivatives
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A very efficient synthesis of 2,3-diaryl-β-amino acid derivatives is realized by a TiCl4/triethylamine-catalyzed Mannich-like reaction of arylacetic or arylthioacetic esters with arylimines. The presence on the arylacetic moiety of an ortho-het
- Bonetti, Andrea,Clerici, Francesca,Foschi, Francesca,Nava, Donatella,Pellegrino, Sara,Penso, Michele,Soave, Raffaella,Gelmi, Maria Luisa
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supporting information
p. 3203 - 3209
(2014/06/09)
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- Synthesis, crystal structure, anti-inflammatory and anti-hyperglycemic activities of novel 3,4-disubstituted 1,2,4-triazol-5(4H)-one derivatives
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A new series of 3,4-disubstituted 1,2,4-triazol-5(4H)-one 5a-r, bearing various methoxyphenyl, fluorophenyl, tolyl and phenyl groups, was synthesized by the dehydrocyclization of hydrazinecarboxamides 4a-r by refluxing in a 2 N sodium hydroxide solution. Hydrazinecarboxamides 4a-r was synthesized via the condensation of the corresponding aralkanoic acid hydrazides, 3a-g, with fluoro-, tolyl- and methoxyphenylisocyanates. The newly synthesized compounds (5ar) were characterized by IR, 1H NMR and 13C NMR analyses. The structure of one compound 5a was determined by single crystal X-ray diffraction analysis. All of the synthesized compounds were screened for their anti-inflammatory and anti-diabetic (α-glucosidase and α-amylase inhibition) activity to identify new drugs that might be useful in preventing damage related to diabetes and inflammation. Compounds 5j, 5k and 5m decrease the expression of type II collagen in a dose dependent manner; similarly 5l decrease the COX-2 expression of rabbit articular chondrocytes in a dose dependent manner possessing potent anti-inflammatory potential while some of derivatives including 5c, 5e, 5g and 5h cause inflammation. Meanwhile, excellent α-glucosidase and moderate α-amylase inhibitory profiles against carbohydrate modulating enzymes were demonstrated by compounds 5b, 5f, 5k and 5q compared to the reference standard acarbose, and compounds 5g, 5h, 5i, 5j, 5l and 5o exhibited moderate to low enzyme inhibition potential among the series.
- Saleem, Muhammad,Yu, Seon-Mi,Rafiq, Muhammad,Kim, Song-Ja,Seo, Sung-Yum,Lee, Ki Hwan
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p. 810 - 823
(2015/04/14)
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- Pd(ii)-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation
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A palladium-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation is described. This protocol provides efficient access to a range of ortho-acyl phenylacetamides, which can be easily converted to 3-isochromanone derivatives. The Royal Society of Chemistry 2013.
- Park, Jihye,Kim, Minyoung,Sharma, Satyasheel,Park, Eonjeong,Kim, Aejin,Lee, Sang Hwi,Kwak, Jong Hwan,Jung, Young Hoon,Kim, In Su
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supporting information
p. 1654 - 1656
(2013/03/14)
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- MODULATORS OF AMYLOID BETA.
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The present invention relates to novel compounds of formula I and therapeutically acceptable salts thereof, their pharmaceutical compositions, processes for making them and their use as therapeutic methods for treatment and/or prevention of various diseases. In particular the invention relates to compounds, which inhibit the Aβ40 and Aβ42 production, increase the Aβ37 and Aβ38 production and maintain the Notch signaling and will be used for treatment and/or prevention of Aβ-related pathologies such as Alzheimer's disease, Downs syndrome and β-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, disorders associated with cognitive impairment, such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
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Page/Page column 165
(2010/06/11)
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- Identification of novel urease inhibitors by high-throughput virtual and in vitro screening
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Ureases are important in both agriculture and human health. Bacterial ureases are directly involved in many farm-field problems and pathological conditions. Here, we report a structure-based virtual screening of an in-house compound bank of about 6000 molecular entities by computational docking and binding free energy calculations followed by in vitro screening. Applied protocol leads to the identification of novel urease inhibitors, which can serve as starting points for structural optimization.
- Abid, Obaid-Ur-Rahman,Babar, Tariq Mahmood,Ali, Farukh Iftakhar,Ahmed, Shahzad,Wadood, Abdul,Rama, Nasim Hasan,Uddin, Reaz,Zaheer-Ul-Haq,Khan, Ajmal,Choudhary, M. Iqbal
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scheme or table
p. 145 - 149
(2010/10/19)
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- FUSED HETEROCYCLIC COMPOUND AND USE THEREOF
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The present invention relates to wherein each symbol is as defined in the specification. The compound has a superior mineral corticoidreceptorantagonistic action and is useful as an agent for the prophylaxis or treatment of hypertension, cardiac failure and the like, a compound having a fused heterocycle, or a prodrug thereof, or a salt thereof; and an agent for the prophylaxis or treatment of hypertension, cardiac failure and the like.
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Page/Page column 330
(2008/06/13)
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- Convenient synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides
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We report a facile one-pot, three-step synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides via condensation of 2-p-methoxybenzylamino-4-acetylpyridine with phenylacetylthioureas.
- Bandarage, Upul K.,Come, Jon H.,Green, Jeremy
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p. 8079 - 8081
(2007/10/03)
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- Nonpeptide inhibitors of measles virus entry
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Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500 000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head-neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-μM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6-3.0 μM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.
- Sun, Aiming,Prussia, Andrew,Zhan, Weiqiang,Murray, Ernest E.,Doyle, Joshua,Cheng, Li-Ting,Yoon, Jeong-Joong,Radchenko, Eugene V.,Palyulin, Vladimir A.,Compans, Richard W.,Liotta, Dennis C.,Plemper, Richard K.,Snyder, James P.
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p. 5080 - 5092
(2007/10/03)
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- 19F-Dehydrocoelenterazine as probe to investigate the active site of symplectin
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Fluorinated dehydrocoelenterazines (F-DCTs) were synthesized to study molecular mechanisms of symplectin; a photoprotein of luminous squid Symplectoteuthis oualaniensis L. F-DCTs reacted with dithiothreitol and glutathione under neutral conditions to give
- Isobe, Minoru,Fujii, Tatsuya,Kuse, Masaki,Miyamoto, Keiichi,Koga, Kazushi
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p. 2117 - 2126
(2007/10/03)
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- 2-amino-7-(1-substituted-2-hydroxyethyl)-3,5-dihydropyrrolo[3,2-D]pyrimidin-4-ones
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The invention relates to the 2-amino-7-(1-substituted-2-hydroxyethyl)-3, 5-dihydro-pyrrolo[3,2-d] pyrimidin-4-ones of formula I and tautomers thereof, wherein Ar represents biaryl, carbocyclic or heterocyclic aryl; pharmaceutically acceptable prodrug este
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- Preparation of 2-amino-7-(1-substituted-2-hydroxyethyl)-3, 5-dihydropyrrolo[3,2-d]pyrimidin-4-ones
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The compounds of formula I wherein Ar represents biaryl, carbocyclic or heterocyclic aryl, are prepared, as substantially pure enantiomers, by (a) condensing a compound of the formula as a substantially pure enantiomer, wherein Ar has meaning as defined a
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