- Comprehensive evaluation of biological effects of pentathiepins on various human cancer cell lines and insights into their mode of action
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Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer
- Wolff, Lisa,Bandaru, Siva Sankar Murthy,Eger, Elias,Lam, Hoai-Nhi,Napierkowski, Martin,Baecker, Daniel,Schulzke, Carola,Bednarski, Patrick J.
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Read Online
- Synthesis, dynamic NMR characterization and XRD studies of novel N,N′-substituted piperazines for bioorthogonal labeling
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Novel, functionalized piperazine derivatives were successfully synthesized and fully characterized by 1H/13C/19F NMR, MS, elemental analysis and lipophilicity. All piperazine compounds occur as conformers resulting from the partial amide double bond. Furthermore, a second conformational shape was observed for all nitro derivatives due to the limited change of the piperazine chair conformation. Therefore, two coalescence points were determined and their resulting activation energy barriers were calculated using 1H NMR. To support this result, single crystals of 1-(4-nitrobenzoyl)piperazine (3a, monoclinic, space group C2/c, a = 24.587(2), b = 7.0726(6), c = 14.171(1) ?, β = 119.257(8)°, V = 2149.9(4) ?3, Z = 4, Dobs = 1.454 g/cm3) and the alkyne derivative 4-(but-3-yn-1-yl)-1-(4-fluorobenzoyl)piperazine (4b, monoclinic, space group P21/n, a = 10.5982(2), b = 8.4705(1), c = 14.8929(3) ?, β = 97.430(1)°, V = 1325.74(4) ?3, Z = 4, Dobs = 1.304 g/cm3) were obtained from a saturated ethyl acetate solution. The rotational conformation of these compounds was also verified by XRD. As proof of concept for future labeling purposes, both nitropiperazines were reacted with [18F]F-. To test the applicability of these compounds as possible 18F-building blocks, two biomolecules were modified and chosen for conjugation either using the Huisgen-click reaction or the traceless Staudinger ligation.
- Mamat, Constantin,Pretze, Marc,Gott, Matthew,K?ckerling, Martin
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Read Online
- Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms
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We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeu
- Mancuso, Francesca,Di Fiore, Anna,De Luca, Laura,Angeli, Andrea,Monti, Simona M.,De Simone, Giuseppina,Supuran, Claudiu T.,Gitto, Rosaria
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supporting information
p. 1000 - 1005
(2020/03/23)
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- TETRAZINES FOR HIGH CLICK CONJUGATION YIELD IN VIVO AND HIGH CLICK RELEASE YIELD
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Disclosed herein are tetrazines substituted with groups that result in a high click conjugation yield in vivo and high click release yields. In one aspect, the invention relates to kits comprising said tetrazines and a dienophile, preferably a trans-cyclo
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Page/Page column 201
(2019/11/19)
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- Discovery of novel Bcr-AblT315I inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety
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As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-AblWT and Bcr-AblT315I kinases with IC50 of 0.043 μM and 0.17 μM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 μM and 5.42 μM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.
- Pan, Xiaoyan,Liang, Liyuan,Sun, Ying,Si, Ru,Zhang, Qingqing,Wang, Jin,Fu, Jia,Zhang, Junjie,Zhang, Jie
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p. 232 - 242
(2019/06/14)
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- NMR-based investigations of acyl-functionalized piperazines concerning their conformational behavior in solution
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Selected N-benzoylated piperazine compounds were synthesized to study their conformational behavior using temperature-dependent 1H NMR spectroscopy. All investigated piperazines occur as conformers at room temperature resulting from the restric
- Wodtke, Robert,Steinberg, Janine,K?ckerling, Martin,L?ser, Reik,Mamat, Constantin
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p. 40921 - 40933
(2019/01/03)
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- N?-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling
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Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N?-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10?000 M-1 s-1, which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.
- Wodtke, Robert,Hauser, Christoph,Ruiz-Gómez, Gloria,J?ckel, Elisabeth,Bauer, David,Lohse, Martin,Wong, Alan,Pufe, Johanna,Ludwig, Friedrich-Alexander,Fischer, Steffen,Hauser, Sandra,Greif, Dieter,Pisabarro, M. Teresa,Pietzsch, Jens,Pietsch, Markus,L?ser, Reik
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supporting information
p. 4528 - 4560
(2018/05/07)
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- Synthesis, characterization, and anti-inflammatory activities of methyl salicylate derivatives bearing piperazine moiety
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In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.
- Li, Jingfen,Yin, Yong,Wang, Lisheng,Liang, Pengyun,Li, Menghua,Liu, Xu,Wu, Lichuan,Yang, Hua
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- Expanding the structural diversity of Bcr-Abl inhibitors: Hybrid molecules based on GNF-2 and Imatinib
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In order to expand the structural diversity of Bcr-Abl inhibitors, twenty hybrids (series E and P) have been synthesized and characterized based on Imatinib and GNF-2. Their biological activities were evaluated in vitro against human leukemia cells. Most compounds exhibited potent antiproliferative activity against K562 cells, especially for compounds E4, E5 and E7. Furthermore, these new hybrids were also screened for Abl kinase inhibitory activity, and some of them inhibited Abl kinase with low micromolar IC50 values. In particular, compound P3 displayed the most potent activity with IC50 value of 0.017 μM comparable with that of Imatinib. Molecular docking studies indicated that these novel hybrids fitted well with the active site of Bcr-Abl. These results suggested the great potential of these compounds as novel Bcr-Abl inhibitors.
- Pan, Xiaoyan,Dong, Jinyun,Shao, Ruili,Su, Ping,Shi, Yaling,Wang, Jinfeng,He, Langchong
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supporting information
p. 4164 - 4168
(2015/11/03)
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- Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)- 2H-phthalazin-1-ones as potent PARP-1 inhibitors
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We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H- phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
- Wang, Ling-Xiao,Zhou, Xin-Bo,Xiao, Meng-Liang,Jiang, Ning,Liu, Feng,Zhou, Wen-Xia,Wang, Xiao-Kui,Zheng, Zhi-Bing,Li, Song
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p. 3739 - 3743
(2014/09/17)
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- Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists
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Optimization of a series of aminomethyl ketone diamine H3R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H3R and demonstrated in vivo H3R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
- Zulli, Allison L.,Aimone, Lisa D.,Mathiasen, Joanne R.,Gruner, John A.,Raddatz, Rita,Bacon, Edward R.,Hudkins, Robert L.
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scheme or table
p. 2807 - 2810
(2012/05/20)
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- Dipeptidyl peptidase-4 inhibitor with β-amino amide scaffold: Synthesis, SAR and biological evaluation
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Inhibitors of dipeptidyl peptidase-4 (DPP4) have been shown to be effective treatments for type 2 diabetes. Several series of β-amino amide containing piperazine derivatives have been prepared and evaluated as a inhibitor of DPP4. Finally compound 5m was selected for further evaluation.
- Kim, Heung Jae,Kwak, Woo Young,Min, Jong Pil,Sung, Si Young,Kim, Ha Dong,Kim, Mi Kyung,Kim, Hae Sun,Park, Kyung Jin,Son, Moon Ho,Kim, Soon Hoe,Lee, Bong Jin
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scheme or table
p. 5545 - 5549
(2012/09/22)
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- CDI-mediated monoacylation of symmetrical diamines and selective acylation of primary amines of unsymmetrical diamines
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A highly efficient and green protocol for monoacylation of symmetrical diamines and chemoselective acylation of primary amines of unsymmetrical diamines has been developed.
- Verma, Sanjeev K.,Ghorpade, Ramarao,Pratap, Ajay,Kaushik
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p. 326 - 329
(2012/04/10)
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- Imidazole-catalyzed monoacylation of symmetrical diamines
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Figure Presented. An imidazole-catalyzed protocol for monoacylation of symmetrical diamines has been developed. The protocol gave selective monoacylation of aliphatic (cyclic and acyclic) primary and secondary diamines. In the reaction, imidazole acts as both catalyst and a leaving group. Different monoacylated piperazines and other diamines were synthesized at room temperature in an ethanol/water solvent system.
- Verma, Sanjeev K.,Acharya,Kaushik
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supporting information; experimental part
p. 4232 - 4235
(2010/11/04)
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- PIPERAZINE COMPOUNDS FOR THE INHIBITION OF HAEMATOPOIETIC PROSTAGLANDIN D SYNTHASE
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The present invention relates to compounds of general formula (I): wherein A, Y, X, n and B are as defined herein; and their use in the treatment and prevention of metabolic disorders, inflammatory conditions, allergic conditions, fever, pain including allodynia and nociception, eating disorders, cachexia, brain injuries, cancer of the genitals, sleep apnoea, cardiovascular disease, flush effect associated with nicotinic acid and related compounds or for the promotion of wound healing. Certain compounds of general formula (I) are new and the invention also relates to these compounds and to their use in medicine.
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Page/Page column 61
(2008/12/04)
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- Direct synthesis of N-acylalkylenediamines from carboxylic acids under mild conditions
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Monoacylated piperazine derivatives were prepared directly from carboxylic acids and piperazine using triphenylphosphine (TPP) and N-bromosuccinimide (NBS) in dichloromethane. Inexpensive and readily available reagents, excellent yields, short reaction times and mild reaction conditions are important features of this method.
- Bandgar,Bettigeri
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p. 2917 - 2924
(2007/10/03)
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- NOVEL QUINAZOLINE DERIVATIVES
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Quinazoline derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof in said formula R1is nitro or halogen; R2and R4are each hydrogen, C1-4alkyl, carboxyl, or C2-5alkoxycarbonyl; R3is hydrogen, amino, optionally substituted C1-4alkyl, C1-4alkanoyl, or C2-5alkoxycarbonyl; W is carbon or nitrogen; and m is 0 to 2.
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- Certain substituted 1-aryl-3-piperazin-1′-yl propanones
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Disclosed are compounds of formula I: wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1and Ar2independently represent aryl groups; and Y is hydrogen; o
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- Synthesis and structure-activity relationships of novel 2-amino alkyl chromones and related derivatives as σ site-selective ligands
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Starting from a random screening showing that 2-[(4- benzylpiperazinyl)methyl] chromone was a selective and potent sigma ligand, a series of analogues were synthesized. Introduction of a substituent on the chromone moiety, replacement of methylenes by carbonyl groups and benzyl by aryl groups decrease the affinity for sigma sites. The result obtained after introduction of various substituents on the aromatic part of the benzyl is strictly depending on the size and on the position of these substituents. Stretching of the carbon chain between the phenyl and the piperazine does not strongly modify the affinity. 2-[4-(4'-methoxy benzyl)1-piperazinyl methyl] chromone has been tested in behavioral tests that permit to believe that such derivatives could be interesting for the treatment of psychosis.
- Baziard-Mouysset, Genevieve,Younes, Salouma,Labssita, Youssef,Payard, Marc,Caignard, Daniel-Henri,Rettori, Marie-Claire,Renard, Pierre,Pfeiffer, Bruno,Guardiola-Lemaitre, Beatrice
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p. 339 - 347
(2007/10/03)
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- Certain substituted 1-aryl-3-piperazin-1'-yl propanones to treat Alzheimer's Disease
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Disclosed are compounds of formula I: STR1 or the pharmaceutically acceptable salts thereof wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1 and Ar2 i
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- Substituted 1-aryl-3-piperazin-1'-yl propanones
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Disclosed are compounds of formula I: STR1 wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1 and Ar2 independently represent aryl groups; and Y is hydr
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- Pharmaceutically-active phthalazine compounds
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Compounds having the formula STR1 wherein R is 2-[1-oxo-(2H)-phthalazinyl], R1, R2, R3, R4, R5, R6, X, Y, m and n have the meanings shown in the description. The compounds of formula I are pharmaceutically active as anti-vasospastic, anti-aggregating, and anti-proliferative agents.
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- ISOINDOLINYL-ALKYL-PIPERAZINES
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The invention is generally concerned with isoindolinyl-alkylpiperazine compounds generally characterized by the formula STR1 wherein X is halogen or trifluoromethyl; n is an integer ranging from 2 to 5; Y is STR2 in which R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano; R 2 is hydrogen, halogen, lower alkyl, lower alkoxy; and R 3 is hydrogen, cyano. These compounds are useful as diuretic and/or antihypertensive agents.
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