- Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents
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A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated. It was found that the anti-proliferation activities of hybrids were better than that of FTS. Compound 10a displayed the strongest antitumor activities with IC50 values of 5.72-9.76 μmol/L and selectively inhibited tumor cell proliferation. In addition, 10a induced tumor cell apoptosis in a dose-dependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Wang, Zhi-Qiang,Chang, Ren-An,Huang, Hai-Ying,Wang, Xue-Min,Wang, Xin-Yang,Chen, Li,Ling, Yong
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Read Online
- Polyamine-Conjugated Nitroxides Are Efficacious Inhibitors of Oxidative Reactions Catalyzed by Endothelial-Localized Myeloperoxidase
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The heme enzyme myeloperoxidase (MPO) is a key mediator of endothelial dysfunction and a therapeutic target in cardiovascular disease. During inflammation, MPO released by circulating leukocytes is internalized by endothelial cells and transcytosed into the subendothelial extracellular matrix of diseased vessels. At this site, MPO mediates endothelial dysfunction by catalytically consuming nitric oxide (NO) and producing reactive oxidants, hypochlorous acid (HOCl) and the nitrogen dioxide radical (?NO2). Accordingly, there is interest in developing MPO inhibitors that effectively target endothelial-localized MPO. Here we studied a series of piperidine nitroxides conjugated to polyamine moieties as novel endothelial-targeted MPO inhibitors. Electron paramagnetic resonance analysis of cell lysates showed that polyamine conjugated nitroxides were efficiently internalized into endothelial cells in a heparan sulfate dependent manner. Nitroxides effectively inhibited the consumption of MPO's substrate hydrogen peroxide (H2O2) and formation of HOCl catalyzed by endothelial-localized MPO, with their efficacy dependent on both nitroxide and conjugated-polyamine structure. Nitroxides also differentially inhibited protein nitration catalyzed by both purified and endothelial-localized MPO, which was dependent on ?NO2 scavenging rather than MPO inhibition. Finally, nitroxides uniformly inhibited the catalytic consumption of NO by MPO in human plasma. These studies show for the first time that nitroxides effectively inhibit local oxidative reactions catalyzed by endothelial-localized MPO. Novel polyamine-conjugated nitroxides, ethylenediamine-TEMPO and putrescine-TEMPO, emerged as efficacious nitroxides uniquely exhibiting high endothelial cell uptake and efficient inhibition of MPO-catalyzed HOCl production, protein nitration, and NO oxidation. Polyamine-conjugated nitroxides represent a versatile class of antioxidant drugs capable of targeting endothelial-localized MPO during vascular inflammation.
- Maiocchi, Sophie,Ku, Jacqueline,Hawtrey, Tom,De Silvestro, Irene,Malle, Ernst,Rees, Martin,Thomas, Shane R.,Morris, Jonathan C.
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Read Online
- Synthesis, electrochemistry, DNA binding and in vitro cytotoxic activity of tripodal ferrocenyl bis-naphthalimide derivatives
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A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized and characterized. All of the bis-naphthalimide derivatives exhibited good DNA binding ability which was confirmed by ethidium bromide (EB) displacement experiment and ultraviolet (UV)-visible absorption titration. And the binding mode of these compounds was proved to be a hybrid binding mode by experiments. The cytotoxicity of synthesized compounds against 4 different human cancer cell lines (EC109, BGC823, SGC7901 and HEPG2) was evaluated by thiazolyl blue tetrazolium bromide (MTT) assay. All of the bis-naphthalimide derivatives exhibited good anticancer activity than the positive control drug (amonafide), which was due to the promotion of reactive oxygen species (ROS) level in test cancer cells by the reversible one-electron redox process of ferrocenyl bis-naphthalimide derivatives. Although there was no obvious relationship between the binding constants and the chain length, the structure cytotoxicity relationship revealed that the linker of n = 3, m = 1 was the best choice for the tested tripodol bis-naphthalimide derivatives. Synopsis: A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized to study the DNA binding ability and the cytotoxicity induced by reactive oxygen species. All of the compounds exhibited good DNA binding ability. And the structure cytotoxicity relationship revealed that the structure of 5h was the best choice.
- Fan, Yan-Ru,Wang, Bo-Jin,Jia, Deng-Guo,Yang, Xin-Bin,Huang, Yu
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Read Online
- Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3
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Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.
- Hoshino, Yoshihiko,Iwabuchi, Yoshiharu,Kuriyama, Yuse,Sasano, Yusuke,Uesugi, Shun-ichiro,Yamaichi, Aoto
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p. 1961 - 1965
(2021/01/04)
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- Design, synthesis and biological evaluation of tyrosinase-targeting PROTACs
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The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.
- Cui, Xin,Deng, Yun,Fu, Dingqiang,Li, Guangxun,Qin, Fengming,Tang, Zhuo,Xu, Yan,Yao, Shaohua,Yuan, Yi
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supporting information
(2021/10/12)
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- PCSK9-INHIBITING COMPOUNDS
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The invention relates to compounds of general formula (I): having inhibitory activity against the PCSK9 enzyme. Said compounds can be used, for example, in the prevention and/or treatment of dyslipidaemia.
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Page/Page column 39
(2021/11/26)
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- Phidianidine A and Synthetic Analogues as Naturally Inspired Marine Antifoulants
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Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms. While these natural antifoulants can be structurally diverse, they often display highly conserved chemistries and physicochemical properties, suggesting a natural marine antifouling pharmacophore. In our current report, we investigate the marine natural product phidianidine A, which displays several chemical properties found in highly potent marine antifoulants. Phidianidine A and synthetic analogues were screened against the settlement and metamorphosis of Amphibalanus improvisus cyprids, and several of the compounds displayed inhibitory activities at low micromolar concentrations with IC50 values down to 0.7 μg/mL observed. The settlement study highlights that phidianidine A is a potent natural antifoulant and that the scaffold can be tuned to generate simpler and improved synthetic analogues. The bioactivity is closely linked to the size of the compound and to its basicity. The study also illustrates that active analogues can be prepared in the absence of the natural constrained 1,2,4-oxadiazole ring. A synthetic lead analogue of phidianidine A was incorporated in a coating and included in antifouling field trials, where it was shown that the coating induced potent inhibition of marine bacteria and microalgae settlement.
- Labriere, Christophe,Elumalai, Vijayaragavan,Staffansson, Jannie,Cervin, Gunnar,Le Norcy, Tiffany,Denardou, Hugo,Réhel, Karine,Moodie, Lindon W. K.,Hellio, Claire,Pavia, Henrik,Hansen, J?rn H.,Svenson, Johan
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p. 3413 - 3423
(2020/11/23)
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- Computationally Driven Structure Optimization, Synthesis, and Biological Evaluation of Imidazole-Based Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibitors
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Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which in turn regulates the circulating low-density lipoprotein cholesterol (LDL-C) level. For this reason, the PCSK9 inhibition, by small molecules or peptides, is a validated therapeutic approach for fighting hypercholesterolemia and cardiovascular diseases. In this field, we have recently reported an imidazole-based peptidomimetic that has shown PCSK9 inhibitory activity in the micromolar range. Here, by applying advanced computational techniques, the binding mechanism of that imidazole peptidomimetic was predicted. Then, among a small set of poly-imidazole analogs, compounds showing the highest theoretical affinity were suitably synthesized, relying on a van Leusen reaction based multicomponent strategy. One compound (named RIm13) displayed a PCSK9 inhibitory activity 10-fold lower than the template compound, and, remarkably, at a concentration of 1 μM, it successfully prevented the LDLR degradation mediated by PCSK9 on HepG2 cells. As well as increasing the LDL uptake at the same concentration, RIm13 represents currently one of the most potent small molecules targeting the PCSK9/LDLR protein-protein interaction.
- Lammi, Carmen,Sgrignani, Jacopo,Arnoldi, Anna,Lesma, Giordano,Spatti, Claudia,Silvani, Alessandra,Grazioso, Giovanni
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supporting information
p. 6163 - 6174
(2019/08/02)
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- Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors
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A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 ± 0.35 μM, 5.72 ± 1.56 μM and 3.55 ± 1.28 μM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.
- Zhang, Li,Chen, Yantao,Liu, Na,Li, Linjuan,Xiao, Senhao,Li, Xiaoliu,Chen, Kaixian,Luo, Cheng,Chen, Shijie,Chen, Hua
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supporting information
p. 649 - 654
(2018/07/31)
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- JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules
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A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP-BSK805, filgotinib, and diaminopyrimidine 8 elucidate the binding poses.
- Newton, Ana S.,Deiana, Luca,Puleo, David E.,Cisneros, José A.,Cutrona, Kara J.,Schlessinger, Joseph,Jorgensen, William L.
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supporting information
p. 614 - 617
(2017/06/13)
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- Synthesis and biological evaluation of piperic acid amides as free radical scavengers and αglucosidase inhibitors
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A series of piperic acid amides (4-24, 29, 30) were synthesized and their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory activities were evaluated. Among the synthesized compounds, the amides 11, 13 and 15, which contain o-methoxyphenol, catechol or 5-hydroxyindole moieties, showed potent DPPH free radical scavenging activity (11: EC50 140 μM; 13: EC50 28 μM; 15: EC50 20 μM). The amides 10, 18 and 23 showed higher inhibitory activity of α-glucosidase (10: IC50 21 μM; 18: IC50 21 μM; 23: IC50 12 μM). These data suggest that the hydrophobicity of the conjugated amines is an important determinant of α-glucosidase inhibitory activity. In addition, the amides 13 and 15 showed both potent DPPH free radical scavenging activity and α-glucosidase inhibitory activity (13: IC50 46 μM; 15: IC50 46 μM). This is the first report identifying the DPPH free radical scavenging and α-glucosidase inhibitory activities of piperic acid amides and suggests that these amides may serve as lead compounds for the development of novel αglucosidase inhibitors with antioxidant activity.
- Takao, Koichi,Miyashiro, Takaki,Sugita, Yoshiaki
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p. 326 - 333
(2015/09/08)
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- Hybrid molecule from Farnesylthiosalicylic acid-diamine and phenylpropenoic acid as Ras-related signaling inhibitor with potent antitumor activities
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Novel series of Farnesylthiosalicylic acid-diamine/phenylpropenoic acid hybrids were designed and synthesized. Their in vitro growth inhibitory assays showed that most compounds displayed strong antiproliferation activity against seven cancer cells. Especially, the new hybrid 12f, by the conjugation of 10a with ferulic acid, could selectively suppress the proliferation of tumor cells and display significantly lower toxicities to normal cells than its intermediate 10a. Furthermore, 12f dose-dependently induced SMMC-7721 cell apoptosis. Additionally, our observations demonstrated that 12f inhibited both Ras-related signaling and phosphorylated NF-κB synergistically, which may be advantageous to the strong antitumor activities of 12f. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Ling, Yong,Wang, Zhiqiang,Wang, Xuemin,Li, Xianghua,Wang, Xinyang,Zhang, Wei,Dai, Hong,Chen, Li,Zhang, Yihua
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p. 145 - 152
(2015/01/30)
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- Flow-mediated synthesis of Boc, Fmoc, and Dd iv monoprotected diamines
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A series of monoprotected aliphatic diamines (21 examples) were synthesized via continuous flow methods. The carbamates and enamines were obtained in 45-91% yields using a 0.5 mm diameter PTFE tubular flow reactor. Using readily accessible protecting group precursors, the procedure serves as an attractive alternative to existing batch-mode synthetic routes by providing direct, multigram access to N-Boc-, N-Fmoc-, and N-Ddiv-protected compounds with productivity indexes of 1.2-3.6 g/h.
- Jong, Thingsoon,Bradley, Mark
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supporting information
p. 422 - 425
(2015/03/03)
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- Polylysine dendrimer contrast agent
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The present invention relates generally to branched macromolecules and their use as imaging or contrast agents. In particular, the invention relates to dendrimers, derived from lysine or lysine analogs, bearing a plurality of functional moieties and their application to imaging techniques in which a disease state may be imaged with a targeted contrast agent.
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Page/Page column 47
(2015/09/28)
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- ENZYMATIC CONJUGATION OF POLYPEPTIDES
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The present application relates to methods for the enzymatic functionalization of immunoglobulins, in particular with drugs. Also disclosed herein are linking reagents, functionalized antibodies, pharmaceutical compositions, and method of treating disease and/or conditions.
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- Tuned-affinity bivalent ligands for the characterization of opioid receptor heteromers
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Opioid receptors, including the μ- and δ-opioid receptors (MOR and DOR), are important targets for the treatment of pain. Although there is mounting evidence that these receptors form heteromers, the functional role of the MOR/DOR heteromer remains unresolved. We have designed and synthesized bivalent ligands as tools to elucidate the functional role of the MOR/DOR heteromer. Our ligands (L2 and L4) are comprised of a compound with low affinity at the DOR tethered to a compound with high affinity at the MOR, with the goal of producing ligands with "tuned affinity" at MOR/DOR heteromers as compared to DOR homomers. Here, we show that both L2 and L4 demonstrate enhanced affinity at MOR/DOR heteromers as compared to DOR homomers, thereby providing unique pharmacological tools to dissect the role of the MOR/DOR heteromer in pain.
- Harvey, Jessica H.,Long, Darcie H.,Whistler, Jennifer L.,England, Pamela M.
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supporting information
p. 640 - 644,5
(2020/08/31)
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- Site-specific protein propargylation using tissue transglutaminase
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Transglutaminases (TGases) catalyse the transamidation of glutamine residues with primary amines. Herein we report the first FRET-based activity assay for the direct detection of the ligation (transamidation) reaction mediated by tissue TGase (TG2). This novel assay was then used in a microtiter plate-based screen of a library of 18 potential amine substrates. From this screen it was discovered that propargyl amine serves as an excellent substrate for TG2. Subsequently, propargyl amine and 2-azidoethyl amine were validated independently as TG2 substrates with KM values of 44 ± 4 μM, and 0.99 ± 0.06 mM, respectively. In a proof-of-principle protein labelling experiment, the protein casein was selectively functionalized with propargyl amine using TG2 and subsequently fluorescently labelled through a dipolar cycloaddition reaction with an azido-fluorescein conjugate. This application demonstrates the strong potential of using TG2 for site-specific protein modification through a combination of enzymatic and bioorthogonal chemistry. The Royal Society of Chemistry 2012.
- Gnaccarini, Claudio,Ben-Tahar, Wajih,Mulani, Amina,Roy, Isabelle,Lubell, William D.,Pelletier, Joelle N.,Keillor, Jeffrey W.
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experimental part
p. 5258 - 5265
(2012/07/28)
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- Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase i (Tdp1)-topoisomerase i (Top1) inhibitors
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Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC 50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors.
- Nguyen, Trung Xuan,Morrell, Andrew,Conda-Sheridan, Martin,Marchand, Christophe,Agama, Keli,Bermingam, Alun,Stephen, Andrew G.,Chergui, Adel,Naumova, Alena,Fisher, Robert,O'Keefe, Barry R.,Pommier, Yves,Cushman, Mark
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scheme or table
p. 4457 - 4478
(2012/08/07)
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- Anti-cancer activity of T-type calcium channel blocker in vivo
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3,4-Dihydroquinazoline 1 as T-type calcium channel blocker was in vivo evaluated against A549 xenograft in BALB/c-nu Slc mice, which exhibited 54% tumor growth inhibition through oral administration of 8 mg/kg of body weight and was slightly less active than doxorubicin (68%). In addition, this compound was also profiled for its acute toxicity to ICR mice to afford oral LD50 value of 1,038 mg/kg of body weight.
- Park, Hang Ah,Jung, Soo Yeon,Lee, So Hyung,Kang, Han Byul,Min, Min Sik,Kim, Jungahn,Choo, Dong Joon,Oh, Chun Rim,Kim, Young Deuk,Lee, Kyung-Tae,Lee, Jae Yeol
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experimental part
p. 3353 - 3358
(2012/05/20)
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- Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure-activity relationships
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The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR.
- Cinelli, Maris A.,Cordero, Brenda,Dexheimer, Thomas S.,Pommier, Yves,Cushman, Mark
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experimental part
p. 7145 - 7155
(2010/03/01)
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- Fluorometric assay for tissue transglutaminase-mediated transamidation activity
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Herein, we report the development of a direct discontinuous fluorometric transamidation assay for determining tissue transglutaminase (TG2) activity. In the assay reaction, TG2 catalyzes the formation of a biotin-fluorophore conjugate, using a fluorescent, high affinity γ-glutamyl donor substrate and a biotinylated amine as a γ-glutamyl acceptor substrate. After the reaction, the conjugate is fixed on streptavidin-coated beads and excess substrate is washed away, allowing the transamidation activity to be quantified by fluorescence measurement. This method was used to detect the activity of as little as 0.6 mU of purified TG2, and can be used for detection of activity from crude cellular lysates. Furthermore, this assay can be used for screening potential inhibitors and synthetic substrates, the latter of which was demonstrated herein.
- Gnaccarini, Claudio,Ben-Tahar, Wajih,Lubell, William D.,Pelletier, Joelle N.,Keillor, Jeffrey W.
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scheme or table
p. 6354 - 6359
(2011/02/26)
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- OXOBENZINDOLIZINOQUINOLINES AND USES THEREOF
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The synthesis of aromathecins, substituted 12H-5,l la-diazadibenzo[b,h]fluoren- 11 -ones is described. Use of these cytotoxic compounds and pharmaceutical compositions containing them for the treatment of cancer is described. Two novel processes for the synthesis of this system and a series of 14-substituted aromathecins as novel cytotoxic, topoisomerase I poisons are described.
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Page/Page column 41; 42
(2009/12/23)
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- 3,4-DIHYDROQUINAZOLINE DERIVATIVES
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The present invention relates to 3,4-dihydroquinazoline derivatives, a process of preparing them and a pharmaceutical composition including them. The 3,4-dihydroquinazoline derivatives of the present invention have excellent T-type calcium channel blocking effect and anti-cancer activity.
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Page/Page column 5; 12-13
(2009/01/20)
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- Novel 4-aminoquinolines active against chloroquine-resistant and sensitive P. falciparum strains that also inhibit botulinum serotype A
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We report on the initial result of the coupling of 4-amino-7- chloroquinoline with steroidal and adamantane constituents to provide small molecules with excellent in vitro antimalarial activities (IC90 (W2) down to 6.74 nM). The same entities also inhibit the botulinum neurotoxin serotype A light chain metalloprotease at low micromolar levels (7-31 μM). Interestingly, structural features imparting increased antimalarial activity also provide increased metalloprotease inhibition, thus allowing for simultaneous compound optimizations against distinct targets.
- ?olaja, Bogdan A.,Opsenica, Dejan,Smith, Kirsten S.,Milhous, Wilbur K.,Terzi?, Nata?a,Opsenica, Igor,Burnett, James C.,Nuss, Jon,Gussio, Rick,Bavari, Sina
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supporting information; scheme or table
p. 4388 - 4391
(2009/08/09)
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- Discovery of potent T-type calcium channel blocker
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The intensive SAR study of 3,4-dihydroquinazoline series led to the most potent compound 10 (KYS05090: IC50 = 41 ± 1 nM) against T-type calcium channel and its potency is nearly comparable to that of Kurtoxin. As a small organic molecule, this compound showed the highest blocking activity reported to date.
- Seo, Han Na,Choi, Ja Youn,Choe, Yun Jeong,Kim, Yoonjee,Rhim, Hyewhon,Lee, So Ha,Kim, Jungahn,Joo, Dong Jun,Lee, Jae Yeol
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p. 5740 - 5743
(2008/03/11)
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- Synthesis and pharmacological testing of polyaminoquinolines as blockers of the apamin-sensitive Ca2+-activated K+ channel (SKCa)
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The synthesis and pharmacological testing of a series of non-peptidic blockers of the SKCa (SK-3) channel is described. Target compounds were designed to mimic the spatial relationships of selected key residues in the energy-minimised structure of the octadecapeptide apamin, which are a highly potent blocker of this channel. Structures consist of a central unit, either a fumaric acid or an aromatic ring, to which are attached two alkylguanidine or two to four alkylaminoquinoline substituents. Potency was tested by the ability to inhibit the SKCa channel-mediated after-hyperpolarization (AHP) in cultured rat sympathetic neurones. It was found that bis-aminoquinoline derivatives are significantly more potent as channel blockers than are the corresponding guanidines. This adds to the earlier evidence that delocalisation of positive charge through the more extensive aminoquinolinium ring system is important for effective channel binding. It was also found that an increase in activity can be gained by the addition of a third aminoquinoline residue to give non-quaternized amines which have submicromolar potencies (IC50 = 0.13-0.36 μM). Extension to four aminoquinoline residues increased the potency to IC50 = 93 nM.
- Fletcher, David I.,Ganellin, C. Robin,Piergentili, Alessandro,Dunn, Philip M.,Jenkinson, Donald H.
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p. 5457 - 5479
(2008/09/18)
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- Synthesis of dimeric acridine derived nucleic acid intercalators
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A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence. Suitably monoprotected 1,ω-alkyldiamines gave upon reaction with 6,9-dichloro-2-methoxyacridine (1) followed by deprotection and reaction with EDTA dianhydride the target molecules. In the presence of ascorbate a reduction of the phage-titer of the MS2 phages by > 8 logarithmic decades was achieved.
- Csuk, René,Brezesinski, Thorsten,G?the, Gunnar,Raschke, Christian,Rei?mann, Stefan
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- Synthesis of 3-substituted bicyclic imidazo[1,2-d][1,2,4]thiadiazoles and tricyclic benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles
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A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent SNAr substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.
- Leung-Toung, Regis,Tam, Tim F.,Zhao, Yanqing,Simpson, Craig D.,Li, Wanren,Desilets, Denis,Karimian, Khashayar
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p. 6230 - 6241
(2007/10/03)
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- Synthesis and biological evaluation of new acinetoferrin homologues for use as iron transport probes in mycobacteria
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Four new acinetoferrin homologues were synthesized using a modular synthetic approach. Two linear and two cyclic imide derivatives were generated and evaluated for growth stimulating behavior in Mycobacterium avium subsp paratuberculosis. The yield for the tandem coupling of a functionalized aminohydroxamic acid motif (2 equiv) to a tert-butyl citrate derivative was significantly improved using DCC and N-hydroxysuccinimide. 1H NMR spectroscopy (CD3OD) provided a convenient method for monitoring the final imidization step in TFA using the doublet patterns between 2.5 and 3.06 ppm. New protocols demonstrated that only a 20% growth enhancement was observed with M. avium subsp. paratuberculosis using the imide of acinetoferrin. Last, a siderophore from Streptomyces pilosus, deferrioxamine B, was shown to cross-feed M. avium subsp. paratuberculosis with the same efficiency as the more costly, native chelator, mycobactin J.
- Gardner, Richard A.,Ghobrial, George,Naser, Saleh A.,Phanstiel IV, Otto
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p. 4933 - 4940
(2007/10/03)
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- Synthesis of pathogen inactivating nucleic acid intercalators
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A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence starting from 1,ω-alkyldiamines. As shown in model screenings, in the presence of ascorbic acid the Fe-complexes of these compounds reduced the phage-titer of MS2-phages by several logarithmic decades.
- Csuk, René,Barthel, Alexander,Brezesinski, Thorsten,Raschke, Christian
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p. 975 - 988
(2007/10/03)
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- Cationic lipids with serine backbone
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The present invention provides cationic lipids with serine backbone, a composition for transferring biologically active molecules into cells and/or tissues comprising said cationic lipids, a process for the manufacture of said lipids, the use of said lipids as constituent of a transfection agent and a method for transferring biologically active molecules into cells and/or into tissues or for gene therapy.
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- SULFONAMIDE DERIVATIVES OF 3-SUBSTITUTED IMIDAZOL[1,2-D] -1,2,4-THIADIAZOLES AND 3-SUBSTITUTED-[1,2,4] THIADIAZOLO[4,5-A] BENZIMIDAZOLE AS INHIBITORS OF FIBRIN CROSS-LINKING AND TRANSGLUTAMINASES
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A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity
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- Sulfonamide derivatives of 3-substituted imidazo[1,2-D]-1,2,4-thiadiazoles and 3-substituted-[1,2,4]thiadiazolo[4,5-A]benzimidazole as inhibitors of fibrin cross-linking and transglutaminases
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A method of inhibiting the activity of transglutaminases containing a cysteine residue comprising administering to a mammal an effective amount of a sulfonamide derivative of imidazo[1,2-d]-1,2,4-thiadiazoles sufficient to inhibit the activity.
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Page/Page column 23
(2008/06/13)
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- Heterocycle derivatives and drugs
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There is provided an excellent novel analgesic having an analgesic effect which is effective widely against a pain including a chronic pain or an allodynia accompanied with herpes zoster by acting on a nociceptin receptor. The present invention relates to a compound represented by the following formula: or a salt thereof. In the formula, X and Y are same or different and each represents a nitrogen atom or CH; R1 represents a hydrogen atom or alkyl and the like; A1 and A2 are same or different and each represents a single bond or a divalent aliphatic hydrocarbon group; Q represents a single bond, cycloalkylene group, phenylene group or divalent heterocyclic group; R2A, R2B, R2C and R2D are same or different and each represents a hydrogen atom, alkyl or phenyl; E represents a ethenylene group or —NRCO— (in which R is hydrogen or alkyl) and the like; R3 represents a phenyl group or a heterocyclic group; R4 and R5 are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, —NR6R7 (in which R6 and R7 are same or different and each represents a hydrogen atom or alkyl) and the like.
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- Substituted quinoxaline derivatives as interleukin-8 receptor antagonists
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Quinoxaline compounds are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as interleukin-8 (IL-8) receptor antagonists and can be used in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as a chemokine-mediated disease selected from psoriasis, or atopic distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases.
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- Selective synthesis of carbamate protected polyamines using alkyl phenyl carbonates
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Utilising alkyl phenyl carbonates, an economical, practical and versatile method for selective Boc, Cbz and Alloc protection of polyamines has been developed. This method allows Boc, Cbz and Alloc protection of primary amines in the presence of secondary amines by reaction of the polyamines with the alkyl phenyl carbonates. Also, this method allows mono carbamate protection of simple symmetrical aliphatic α,ω-alkanediamines in high yields with respect to the diamine. Finally, the method allows selective carbamate protection of a primary amine located on a primary carbon in the presence of a primary amine located on a secondary or a tertiary carbon in excellent yields.
- Pittelkow, Michael,Lewinsky, Rasmus,Christensen, Jorn Bolstad
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p. 2195 - 2202
(2007/10/03)
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- Parallel combinatorial synthesis of glycodendrimers and their hydrogelation properties
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A series of glycodendrons has been assembled using a parallel combinatorial approach, and it has been shown that subtle structural variations between dendrons give rise to significant differences in their hydrogelation behavior.
- McWatt, Martin,Boons, Geert-Jan
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p. 2535 - 2545
(2007/10/03)
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- Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the β-turn
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A library of 951 compounds based upon the β-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compound EL1 with racemic Nal(2') in the i + 1 position, DPro in the i + 2 position, and Trp in the i + 3 position possesses an EC50 of 42.5 ± 6.9 μM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC50 value of 63.4 ± 26.9 μM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a β-turn conformation involving the melanocortin 'Phe-Arg-Trp' core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.
- Haskell-Luevano, Carrie,Rosenquist, ?sa,Souers, Andrew,Khong, Kathy C.,Ellman, Jonathon A.,Cone, Roger D.
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p. 4380 - 4387
(2007/10/03)
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- Total synthesis of NPTX-5 and NPTX-6, Joro spider (Nephila clavata) toxins having a unique putreanine trimer and putreanine tetramer acylpolyamine chain
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The first total synthesis of NPTX-5 and NPTX-6, Joro spider (Nephila clavata) toxins having a 4-hydroxyindole nucleus and a unique putreanine trimer and tetramer acylpolyamine chain, respectively, has been achieved by the iterative use of a key azide compound.
- Saito, Hiroaki,Yuri, Etsuko,Miyazawa, Masahiro,Itagaki, Yasuhiro,Nakajima, Terumi,Miyashita, Masaaki
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p. 6479 - 6482
(2007/10/03)
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- A Constrained Diketopiperazine as a New Scaffold for the Synthesis of Peptidomimetics
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As a new scaffold for peptidomimetic synthesis, a highly constrained bifunctional diketopiperazine, 4, has been prepared by smooth N-alkylation with tert-butyl bromoacetate. As a first application, we describe herein the synthesis of new peptidomimetics of the Arg-Gly-Asp (RGD) sequence. The product 30, which shows a selective platelet-aggregation inhibiting activity, can be used as a lead for the preparation of more potent products.
- Pons, Jean-Francois,Fauchere, Jean-Luc,Lamaty, Frederic,Molla, Annie,Lazaro, Rene
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p. 853 - 859
(2007/10/03)
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- Total synthesis of Nephilatoxin-1 (NPTX-1), a Joro spider (Nephila clavata) toxin having a 4-hydroxyindole nucleus
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The first total synthesis of Nephilatoxin-1 (NPTX-1), a Joro spider (Nephila clavata) toxin having a 4-hydroxyindole nucleus, has been achieved by using two key azide intermediates.
- Miyashita, Masaaki,Saito, Hiroaki,Matsushita, Masayuki,Miyazawa, Masahiro,Itagaki, Yasuhiro,Nakajima, Terumi
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p. 8297 - 8298
(2007/10/03)
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- A novel radioiodination reagent for protein radiopharmaceuticals with L- lysine as a plasma-stable metabolizable linkage to liberate m-iodohippuric acid after lysosomal proteolysis
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Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptide after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L- HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteloysis in hepatic cells were investigated after conjugation of [131I]-L-HML iwht galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I-L-HML- NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murien liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.
- Wakisaka, Kouji,Arano, Yasushi,Uezono, Takashi,Akizawa, Hiromichi,Ono, Masahiro,Kawai, Keiichi,Ohomomo, Yoshiro,Nakayama, Morio,Saji, Hideo
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p. 2643 - 2652
(2007/10/03)
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- Synthesis of Carbamate Protected Spermidine Homologues Through α,ω-Alkanediamines
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The total synthesis of three triamines selectively protected in the primary amino groups (1a-c) and two triamines protected in the secondary amino function and in one of the primary amino functions (2a and 2c), based on a simple and efficient procedure, is described.
- Arasujo, M. Joso S. M. P.,Ragnarsson, Ulf,Trigo, M. Joaquina S. A. Amaral,Almeida, M. Lurdes S.
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p. 2143 - 2161
(2007/10/03)
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- Practical, convergent total synthesis of polyamine amide spider toxin NSTX-3
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A practical, total synthesis of polyamine amide spider toxin NSTX-3, a potent glutamate receptor antagonist with potential as a neuroprotective agent, is reported. The unsymmetrical polyamine moiety was built by a conjugate addition to afford putreanine and regioselective acylation of L-asparaginyl-cadaverine.
- Blagbrough, Ian S.,Moya, Eduardo,Walford, Steven P.
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p. 551 - 554
(2007/10/02)
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- Amide compounds, their production and use
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Amide compounds having glutamate receptor-inhibiting activity and having the formula: STR1 (wherein R1 and R2 each is hydrogen atom, an alkyl group or an acyl group, or STR2 is a cyclic amino group, m is an integer of 1 to 3, n is an integer of 0 to 4, x is an integer of 2 to 6 and y is an integer of 0 to 3) or salts thereof, are provided. The compounds are useful as a medicine for therapy or/and prevention of sequelae of cerebral apoplexy in warm-blooded animals.
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- Mono-protected Diamines. N-tert-Butoxycarbonyl-α,ω-alkanediamines from α,ω-Alkanediamines
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We wish to report a convenient pathway to N-tert-butoxycarbonyl-α,ω-alanediamines 2a-e by treatment of the corresponding α,ω-alkanediamine with di-tert-butyl dicarbonate in dioxane as the solvent.Only small amounts of the bis-substituted N,N'-tert-butoxycarbonyl-α,ω-aldnediamines 3a-e were formed (2-9percent) which were easily removed by an aquous workup.The α,ω-alkane-aza-diamine 4 was also mono-protected (62percent yield of 5) by the same methodology.
- Krapcho, A. Paul,Kuell, Christopher S.
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p. 2559 - 2564
(2007/10/02)
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- Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity
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Several polymethylene tetraamines related to the methoctramine (1) were prepared and evaluated for their blocking activity on M-2 muscarinic receptors in guinea pig atria and ileum. It turned out that antimuscarinic potency depends on the following parameters: (a) nature of the substituent on both inner and outer nitrogens and (b) carbon chain length separating the inner nitrogens as well as the inner and outer nitrogens. Optimum activity at cardiac M-2 muscarinic receptors was associated with the chain lengths present in 1, that is, eight methylenes between the inner nitrogens and six methylenes between the inner and outer nitrogens. With regard to the substituents, replacement of the benzylic moiety of 1 by a 2-furyl or a 5-methyl-2-furyl nucleus resulted in enhanced potency toward cardiac M-2 muscarinic receptors. In fact, furtramine (18) and mefurtramine (19) proved to be more potent and more selective than 1. Moreover, N-methylation of the four nitrogens of 1 gave different effects: methylation of the outer nitrogens, giving 22, caused a significant decrease in activity whereas methylation of the inner nitrogens, yielding 23, resulted in an increase in activity in both atria and ileum.
- Melchiorre,Quaglia,Picchio,Giardina,Brasili,Angeli
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