- Designing the polyamine pharmacophore: Influence of N-substituents on the transport behavior of polyamine conjugates
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N-Ethylated N-arylmethyl polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT). To understand the effect of N-ethylation upon PAT selectivity, ethyl groups were appended onto a PAT-selective N1-anthracenenylmethyl homospermidine derivative. 1b. Bioevaluation in L1210 murine leukemia cells and in two Chinese hamster ovary cell lines (PAT-active CHO and PAT-deficient CHO-MG) revealed a dramatic decrease in PAT targeting ability upon N1 or N5 ethylation of the pharmacophore 1b. Experiments using the amine oxidase inhibitor, aminoguanidine (AG, 2 mM), revealed that the N9-ethyl and N9-methyl analogues were able to retain their PAT selectivity and cytotoxicity properties in the presence or absence of AG. In contrast, the lead compound 1b (containing a terminal NH2 group) revealed a dramatic reduction in both its PAT-targeting ability and cytotoxicity in the absence of AG. An improved balance between these three properties of PAT-targeting, cytotoxicity and metabolic stability can be attained via N-methylation at the N9-position.
- Kaur, Navneet,Deleros, Jean-Guy,Archer, Jennifer,Weagraff, Nathan Z.,Martin, Bénédicte,Phanstiel IV, Otto
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- Synthesis and biological properties of Quilamines II, new iron chelators with antiproliferative activities
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To selectively target tumor cells expressing an overactive Polyamine Transport System (PTS), we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, derived from the lead compound HQ1-44, which we named Quilamines II. The structures of four new antiproliferative agents were developed. They differ in the size of the linker (HQ0-44 and HQ2-44) or in the nature of the linker (HQCO-44 and HQCS-44) between a hydroxyquinoline moiety (HQ) and a homospermidine (44) chain, the best polyamine vector. The Quilamines II were obtained after 6 to 9 steps by Michael addition, peptide linkage, and reductive amination or by using the Willgerodt-Kindler reaction. The biological evaluation of these second-generation Quilamines showed that modifying the size of the linker increased the selectivity of these compounds for the PTS. In addition, measurement of the toxicity of Quilamines HQ0-44 and HQ2-44 highlighted their marked antiproliferative nature on several cancerous cell lines as well as a differential activity on nontransformed cells (fibroblasts). In contrast, Quilamines HQCO-44 and HQCS-44 presented low selectivity for the PTS, probably due to a loss of electrostatic interaction. We also demonstrated that the HCT116 cell line, originating from a human colon adenocarcinoma, was the most responsive to the various Quilamines. As deduced from the calcein and HVA assays, the higher iron chelating capacity of HQ1-44 could explain its higher antiproliferative efficiency.
- Corcé, Vincent,Renaud, Stéphanie,Cannie, Isabelle,Julienne, Karine,Gouin, Sébastien G.,Loréal, Olivier,Gaboriau, Fran?ois,Deniaud, David
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- Synthesis and structure-property relationship of polyester-urethanes and their evaluation for the regeneration of contractile tissues
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The structure-property relationship of degradable polyurethanes from non toxic building blocks was studied by synthesising four different biodegradable poly(ester urethanes) from poly(s-caprolactone) (PCL) diol, 1,4- diisocyanatobutane and different chain extenders. For instance, the chain extenders were an amino acid derivative diamine, an amino acid derivative diol, a cyclic diol and a custom made diamine, containing an enzymatically degradable peptide (Ala-Ala sequence). Physicochemical and morphological characterisation (SEC, DSC, DMA, AFM) was performed, showing the influence of the chain extender on the polyurethane properties. A correlation between surface domain morphologies and thermal properties was highlighted and a relationship between the biological response and surface morphologies was observed. Collecting mechanical characterisation and myoblast cell culture results together, the polyurethane synthesised with the amino acid derivative diamine resulted the most promising candidate for fabricating scaffolds supporting the regeneration of muscle tissues.
- Sartori, Susanna,Boffito, Monica,Serafini, Piero,Caporale, Andrea,Silvestri, Antonella,Bernardi, Ettore,Sassi, Maria Paola,Boccafoschi, Francesca,Ciardelli, Gianluca
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- Selective alkylation of T-T mismatched DNA using vinyldiaminotriazine-acridine conjugate
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The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T-T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)-acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T-T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1(DM1), the observed reaction rate for one alkylation increased in proportion to the number of T-T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT-acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1.
- Onizuka, Kazumitsu,Usami, Akira,Yamaoki, Yudai,Kobayashi, Tomohito,Hazemi, Madoka E.,Chikuni, Tomoko,Sato, Norihiro,Sasaki, Kaname,Katahira, Masato,Nagatsugi, Fumi
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- Ion pairing between the chain ends induces folding of a flexible zwitterion in methanol
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A well defined folded loop structure can be induced in a flexible zwitterion 10 in the polar and protic solvent methanol by charge interactions between the two termini of the zwitterion. In 10 a (guanidiniocarbonyl)pyrrole moiety, a highly efficient oxoan
- Schmuck, Carsten,Dudaczek, Juergen
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- Prospective study directed to the synthesis of unsymmetrical linked bis-5-arylidene rhodanine derivatives via "one-pot two steps" reactions under microwave irradiation with their antitumor activity
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We here report on the synthesis of new unsymmetrical linked bis-5-arylidene rhodanine derivatives with stereocontrolled Z-configuration. The 6 steps synthesis was achieved and the key steps are the construction of the two 5-arylidene rhodanine moieties using an "one-pot two-steps" method under microwave dielectric heating in a closed reactor. The intermediates 6, 7 and desired unsymmetrical compounds 9 have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT116, and NCI-H727 tumoral cell lines). Two of all compounds have shown potent activity against Huh7 D12, Caco2, and MDA-MB 231. Graphical Abstract: [Figure not available: see fulltext.].
- Coulibaly, Wacothon Karime,Paquin, Ludovic,Bénie, Anoubilé,Békro, Yves-Alain,Le Guével, Rémy,Ravache, Myriam,Corlu, Anne,Bazureau, Jean Pierre
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- Potentiation of BCNU cytotoxicity by molecules targeting abasic lesions in DNA
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We describe the synthesis, DNA binding measurements and pharmacological properties of a series of new heterodimeric molecules, in which a 2,6-diaminopurine is linked to a 9-aminoacridine chrimophore. The linking chain contains a central N,N′-disubstituted guanidine, connected to the two chromophores by polymethylenic units of variable length. Copyright
- Alarcon, Karine,Demeunynck, Martine,Lhomme, Jean,Carrez, Danièle,Croisy, Alain
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- Peptoid Library Agar Diffusion (PLAD) Assay for the High-Throughput Identification of Antimicrobial Peptoids
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Rapid emergence of antimicrobial resistant organisms necessitates equally rapid methods for the development of new antimicrobial compounds. Of recent interest have been mimics of antimicrobial peptides known as antimicrobial peptoids, which exhibit simila
- Fisher, Kevin J.,Turkett, Jeremy A.,Corson, Ashley E.,Bicker, Kevin L.
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- Synthesis and characterization of segmented copoly(ether urea)s with uniform hard segments
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Employing protective group strategy and novel isocyanate chemistry, segmented copoly-(ether urea)s with uniform hard segments were prepared. Amine-terminated poly(tetrahydrofuran) served as the soft segment of these polymers. The size of the hard segments and the number of urea groups it contains were varied systematically, and their influence on the properties was investigated. The strength of hydrogen bonding between the urea groups in monodisperse hard segments containing exactly 1 to exactly 4 urea groups was studied by infrared spectroscopy and compared with materials containing polydisperse hard segments. The strength of hydrogen bonding in polymers possessing exactly two urea groups per hard segment resulted in an optimal balance between excellent mechanical properties and good processability and solubility.
- Versteegen, Ron M.,Sijbesma, Rint P.,Meijer
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- An attempt to chemically state the cross-talk between monomers of COX homodimers by double/hybrid inhibitors mofezolac-spacer-mofezolac and mofezolac-spacer-arachidonic acid
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Cardiovascular diseases (CVDs) account for over 17 million death globally each year, including arterial thrombosis. Platelets are key components in the pathogenesis of this disease and modulating their activity is an effective strategy to treat such throm
- Perrone, Maria Grazia,Miciaccia, Morena,Vitale, Paola,Ferorelli, Savina,Araújo, Cristina da Costa Bernardes,de Almeida, Gabriella Silva,Souza Domingos, Thaisa Francielle,da Silva, Luiz Claudio Rodrigues Pereira,de Pádula, Marcelo,Cabral, Lucio Mendes,Sathler, Plínio Cunha,Bonaccorso, Carmela,Fortuna, Cosimo G.,Scilimati, Antonio
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- New methods for side-chain protection of cysteine
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Matrix presented Cysteine sulfhydryl protection with either the Fmoc or the Fm group was accomplished in one step and in high yield using commercially available FmocCl or FmocOSu, respectively. Mechanisms for the Fmoc to Fm transformations are discussed.
- West, Christopher W.,Estiarte, M. Angels,Rich, Daniel H.
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- 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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p. 1681 - 1692
(2021/06/28)
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- ATP13A3 is a major component of the enigmatic mammalian polyamine transport system
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Polyamines, such as putrescine, spermidine, and spermine, are physiologically important polycations, but the transporters responsible for their uptake in mammalian cells remain poorly characterized. Here, we reveal a new component of the mammalian polyamine transport system using CHO-MG cells, a widely used model to study alternative polyamine uptake routes and characterize polyamine transport inhibitors for therapy. CHO-MG cells present polyamine uptake deficiency and resistance to a toxic polyamine biosynthesis inhibitor methylglyoxal bis-(guanylhydrazone) (MGBG), but the molecular defects responsible for these cellular characteristics remain unknown. By genome sequencing of CHO-MG cells, we identified mutations in an unexplored gene, ATP13A3, and found disturbed mRNA and protein expression. ATP13A3 encodes for an orphan P5B-ATPase (ATP13A3), a P-type transport ATPase that represents a candidate polyamine transporter. Interestingly, ATP13A3 complemented the putrescine transport deficiency and MGBG resistance of CHO-MG cells, whereas its knockdown in WT cells induced a CHO-MG phenotype demonstrated as a decrease in putrescine uptake and MGBG sensitivity. Taken together, our findings identify ATP13A3, which has been previously genetically linked with pulmonary arterial hypertension, as a major component of the mammalian polyamine transport system that confers sensitivity to MGBG.
- Hamouda, Norin Nabil,van den Haute, Chris,Vanhoutte, Roeland,Sannerud, Ragna,Azfar, Mujahid,Mayer, Rupert,Calabuig, álvaro Cortés,Swinnen, Johannes V.,Agostinis, Patrizia,Baekelandt, Veerle,Annaert, Wim,Impens, Francis,Verhelst, Steven H.L.,Eggermont, Jan,Martin, Shaun,Vangheluwe, Peter
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- Synthesis process of spermidine and intermediate thereof
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The invention provides a synthesis process of spermidine (I) which takes 3 -t-butyloxycarbonyl V (N -) and -1-t-butyloxycarbonyl 4 - IV butanediamine (N -) as a raw material to obtain the spermidine trihydrochloride (-4 - II III) by reductive amination reaction, and provides a novel method for chemical synthesis of spermidine by liberation of the protecting group from the intermediate I (3 -) to obtain the spermidine (III) II.
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Paragraph 0030-0032
(2021/10/27)
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- 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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- Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy in Vitro and in Vivo in an Alzheimer's Disease Mouse Model
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A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
- Scheiner, Matthias,Hoffmann, Matthias,He, Feng,Poeta, Eleonora,Chatonnet, Arnaud,Monti, Barbara,Maurice, Tangui,Decker, Michael
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p. 9302 - 9320
(2021/07/19)
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- Synthesis and antileishmanial activity of 1,2,4,5-tetraoxanes against leishmania donovani
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A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 μm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 μm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.
- Cabral, Lília I.L.,Pomel, Sébastien,Cojean, Sandrine,Amado, Patrícia S.M.,Loiseau, Philippe M.,Cristiano, Maria L.S.
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supporting information
(2020/02/11)
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- NEW ENDOPEROXIDE COMPOUNDS, PROCESS FOR OBTAINING THEM AND USES THEREOF FOR CONTROL OF PERKINSIOSIS IN BIVALVES
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The present invention relates to new endoperoxide compounds and compositions, and to a process for producing them for prophylaxis and control of perkinsiosis in bivalves. Endoperoxide compounds with biological activity against Perkinsus olseni include 13
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Page/Page column 23
(2020/12/11)
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- Fluorescent H2Receptor Squaramide-Type Antagonists: Synthesis, Characterization, and Applications
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Fluorescence labeled ligands have been gaining importance as molecular tools, enabling receptor-ligand-binding studies by various fluorescence-based techniques. Aiming at red-emitting fluorescent ligands for the hH2R, a series of squaramides labeled with pyridinium or cyanine fluorophores (19-27) was synthesized and characterized. The highest hH2R affinities in radioligand competition binding assays were obtained in the case of pyridinium labeled antagonists 19-21 (pKi: 7.71-7.76) and cyanine labeled antagonists 23 and 25 (pKi: 7.67, 7.11). These fluorescent ligands proved to be useful tools for binding studies (saturation and competition binding as well as kinetic experiments), using confocal microscopy, flow cytometry, and high content imaging. Saturation binding experiments revealed pKd values comparable to the pKi values. The fluorescent probes 21, 23, and 25 could be used to localize H2 receptors in HEK cells and to determine the binding affinities of unlabeled compounds.
- Alencastre, Inês,Bernhardt, Günther,Biselli, Sabrina,Buschauer, Armin,Chen, Mengya,Erdmann, Daniela,Gomez-Lazaro, Maria,Keller, Max,Lamghari, Meriem,Littmann, Timo,Maia, André F.,Ozawa, Takeaki,Tanaka, Miho,Tropmann, Katharina
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supporting information
p. 1521 - 1528
(2020/09/15)
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- Structure-activity relationships and mechanistic studies of novel mitochondria-targeted, leishmanicidal derivatives of the 4-aminostyrylquinoline scaffold
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A new class of quinoline derivatives, bearing amino chains at C-4 and a styryl group at C-2, were tested on Leishmania donovani promastigotes and axenic and intracellular Leishmania pifanoi amastigotes. The introduction of the C-4 substituent improves the activity, which is due to interference with the mitochondrial activity of the parasite and its concomitant bioenergetic collapse by ATP exhaustion. Some compounds show a promising antileishmanial profile, with low micromolar or submicromolar activity on promastigote and amastigote forms and a good selectivity index.
- Staderini, Matteo,Piquero, Marta,Abengózar, María ángeles,Nachér-Vázquez, Montserrat,Romanelli, Giulia,López-Alvarado, Pilar,Rivas, Luis,Bolognesi, Maria Laura,Menéndez, J. Carlos
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supporting information
p. 38 - 53
(2019/03/26)
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- Chiral recognition of carboxylate anions by (R)-BiNoL-based macrocyclic receptors
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Three (R)-BINOL-based macrocyclic receptors obtained via double-amidation reaction were used for chiral recognition of four anions derived from α-hydroxy and α-amino acids. The structural factors of hosts and guests that affect chiral recognition processes were also investigated, indicating that the proper geometry of both receptor and guest molecules plays a crucial role in effective enantio-discrimination.
- Tyszka-Gumkowska, Agata,Pikus, Grzegorz,Jurczak, Janusz
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supporting information
(2019/08/01)
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- The Total Synthesis of Spermine Alkaloid Kukoamine Bimesylate
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The first total synthesis of kukoamine B bimesylate was completed from 1,4-diaminobutane dihydrochloride in 12 steps with a 11.4% overall yield, and all the steps could be carried out at a kilogram scale. The cyano groups were used as the precursor of amino groups to avoid the competitive reaction delicately. The aza-Michael addition reaction, amidation and hydrogenation of the cyano group sequence was streamlined as a general approach towards the synthesis of polyamine structures.
- Dong, Kai
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supporting information
p. 2669 - 2672
(2018/12/14)
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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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- Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels
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Ryanodine receptor (RyR) Ca2+-release channels are essential for contraction in skeletal and cardiac muscle and are prime targets for modification of contraction in disorders that affect either the skeletal or heart musculature. We designed and synthesized a number of compounds with structures based on a naturally occurring peptide (A peptides) that modifies the activity of RyRs. In total, 34 compounds belonging to eight different classes were prepared. The compounds were screened for their ability to enhance Ca2+ release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca2+ release. Competition studies with the parent peptides indicated that the synthetic compounds act at a competing site. The activity of the most effective of the compounds, BIT 180, was further explored using Ca2+ release from skeletal SR vesicles and contraction in intact skeletal muscle fibers. The compounds did not alter tension in intact fibers, indicating that (as expected) they are not membrane permeable, but importantly, that they are not toxic to the intact cells. Proof in principal that the compounds would be effective in intact muscle fibers if rendered membrane permeable was obtained with a structurally related membrane-permeable scorpion toxin (imperatoxin A), which was found to enhance contraction.
- Robinson, Ken,Easton, Christopher J.,Dulhunty, Angela F.,Casarotto, Marco G.
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p. 1957 - 1971
(2018/09/11)
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- Convenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular SNAr reactions
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Benzodiazepinones are an important family of heterocycles with very attractive pharmacological properties and peptidomimetic abilities. We report herein a rapid and efficient two-step synthesis of polysubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones using a multicomponent condensation/cyclization strategy. The approach uses an Ugi four-component reaction to condense readily available Nα-Fmoc-amino acids, amines and isocyanides with a 2-fluorobenzaldehyde derivative followed by a one-pot Fmoc-group removal, intramolecular aromatic nucleophilic substitution for ring closure and side chain deprotection. The described method gives access to benzo-fused 7- and 8-membered rings bearing a wide variety of functionalized substituents and was applied to efficiently prepare tri- and tetrasubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones in high yields in two straightforward steps.
- Vézina-Dawod, Simon,Gerber, Nicolas,Liang, Xinxia,Biron, Eric
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supporting information
p. 6347 - 6355
(2017/09/28)
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- INHIBITORS FOR PROLIFERATING CELL NUCLEAR ANTIGEN AND USES
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The present invention relates to series of compounds as an inhibitor targeting Proliferating Cell Nuclear Antigen (PCNA). Pharmaceutical compositions of those compounds and methods of using them in the treatment of cancer are within the scope of this disclosure.
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Paragraph 00131
(2017/07/06)
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- Synthetic method of artificial selenium enzyme
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The invention discloses a synthetic method of artificial selenium enzyme and relates to a synthetic method of a compound. The synthetic method mainly comprises three steps of synthesis of a double-seleniumcompound with a benzene ring, synthesis of a butan
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Paragraph 0021; 0022; 0023; 0024
(2017/07/20)
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- Assay for High-Throughput Identification of Therapeutic Compounds
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A solid supported branched linker assay system, including an alpha compound and a beta compounds reversibly tethered to a solid support; a branched linker coupled to the solid support that tethers the alpha and beta compounds to the solid support; the bra
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Paragraph 0146-0147
(2017/09/29)
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- Diversity-oriented synthesis and cytotoxic activity evaluation of biaryl-containing macrocycles
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Synthesis of biaryl-containing macrocycles has been carried out through a four-step approach comprising two Ugi four component reactions and a Suzuki-Miyaura macrocyclization. This protocol allowed the synthesis of 12- and 14-membered macrocycles. Cytotoxic activity evaluation showed that some of the molecules were effective against leukemia, glioblastoma and lung cancer cell lines (IC50 = 4.0, 5.9 and 7.6, respectively).
- Pérez-Labrada, Karell,Cruz-Mendoza, Marco A.,Chávez-Riveros, Alejandra,Hernández-Vázquez, Eduardo,Torroba, Tomás,Miranda, Luis D.
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p. 2450 - 2458
(2017/03/20)
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- Naphthalene diimide-polyamine hybrids as antiproliferative agents: Focus on the architecture of the polyamine chains
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Naphthalene diimides (NDIs) have been widely used as scaffold to design DNA-directed agents able to target peculiar DNA secondary arrangements endowed with relevant biochemical roles. Recently, we have reported disubstituted linear- and macrocyclic-NDIs that bind telomeric and non-telomeric G-quadruplex with high degree of affinity and selectivity. Herein, the synthesis, biological evaluation and molecular modelling studies of a series of asymmetrically substituted NDIs are reported. Among these, compound 9 emerges as the most interesting of the series being able to bind telomeric G-quadruplex (ΔTm = 29 °C at 2.5 μM), to inhibit the activity of DNA processing enzymes, such as topoisomerase II and TAQ-polymerase, and to exert antiproliferative effects in the NCI panel of cancer cell lines with GI50values in the micro-to nanomolar concentration range (i.e. SR cell line, GI50= 76 nM). Molecular mechanisms of cell death have been investigated and molecular modelling studies have been performed in order to shed light on the antiproliferative and DNA-recognition processes.
- Milelli, Andrea,Marchetti, Chiara,Greco, Maria Laura,Moraca, Federica,Costa, Giosuè,Turrini, Eleonora,Catanzaro, Elena,Betari, Nibal,Calcabrini, Cinzia,Sissi, Claudia,Alcaro, Stefano,Fimognari, Carmela,Tumiatti, Vincenzo,Minarini, Anna
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p. 107 - 122
(2017/02/10)
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- Naphthoquinone amino acid derivatives, synthesis and biological activity as proteasome inhibitors
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The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC50 values in the sub-μm range.
- Marastoni, Mauro,Trapella, Claudio,Scotti, Alessandra,Fantinati, Anna,Ferretti, Valeria,Marzola, Erika,Eleonora, Gallerani,Gavioli, Riccardo,Preti, Delia
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p. 865 - 877
(2017/07/04)
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- From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis
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Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.
- Devine, William G.,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas, Domingo,Satoh, Takashi,Tear, Westley,Ranade, Ranae M.,Barros-álvarez, Ximena,Hol, Wim G. J.,Buckner, Frederick S.,Navarro, Miguel,Pollastri, Michael P.
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p. 225 - 236
(2017/04/21)
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- Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria
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Infections caused by multidrug-resistant bacteria are on the rise and, therefore, new antimicrobial agents are required to prevent the onset of a postantibiotic era. In this study, we develop new antimicrobial compounds in the form of single-chain polymeric nanoparticles (SCPNs) that exhibit excellent antimicrobial activity against Gram-negative bacteria (e.g., Pseudomonas aeruginosa) at micromolar concentrations (e.g., 1.4 μM) and remarkably kill ≥99.99% of both planktonic cells and biofilm within an hour. Linear random copolymers, which comprise oligoethylene glycol (OEG), hydrophobic, and amine groups, undergo self-folding in aqueous systems due to intramolecular hydrophobic interactions to yield these SCPNs. By systematically varying the hydrophobicity of the polymer, we can tune the extent of cell membrane wall disruption, which in turn governs the antimicrobial activity and rate of resistance acquisition in bacteria. We also show that the incorporation of OEG groups into the polymer design is essential in preventing complexation with proteins in biological medium, thereby maintaining the antimicrobial efficacy of the compound even in in vivo mimicking conditions. In comparison to the last-resort antibiotic colistin, our lead agents have a higher therapeutic index (by ca. 2-3 times) and hence better biocompatibility. We believe that the SCPNs developed here have potential for clinical applications and the information pertaining to their structure-activity relationship will be valuable toward the general design of synthetic antimicrobial (macro)molecules.
- Nguyen, Thuy-Khanh,Lam, Shu Jie,Ho, Kitty K. K.,Kumar, Naresh,Qiao, Greg G.,Egan, Suhelen,Boyer, Cyrille,Wong, Edgar H. H.
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p. 237 - 248
(2017/04/21)
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- Hypoboric acid derivative based on 2-(4-dyhydroxy borane)pheoylquinoline-4-carboxylic acid and preparation method and application thereof
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The invention discloses a hypoboric acid derivative based on 2-(4-dyhydroxy borane)pheoylquinoline-4-carboxylic acid and a preparation method thereof. The hypoboric acid derivative is used for preparing catecholamine and carbohydrate fluorescent probes. T
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Paragraph 0026; 0027
(2017/07/19)
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- Diamines compound single-Boc protection method
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The invention relates to a diamines compound single-Boc protection method. The method includes following steps: enabling t-butylazidoformate and the diamines compound to react in an organic solvent at 0-30 DEG C to obtain a single-Boc-protected diamines compound. T-butylazidoformate is used as a Boc protection reagent, so that reaction selectivity can be improved effectively; a byproduct is nitrogen which escapes directly from a reaction system. By the method, the defect that a byproduct-isobutene is generated when Boc anhydride is taken as a raw material is overcome, and the problems of thick reaction system and difficulty in purification are solved thoroughly. The method is high in reaction efficiency, simple in aftertreatment and suitable for industrial production.
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-
Paragraph 0038; 0040
(2017/08/31)
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- MOFEZOLAC DERIVATIVES AS MULTI-FUNCTIONS SELECTIVE COX-1 INHIBITORS
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The invention relates to a new class of compounds of formula (I) targeting COX-1. The invention also relates to the use of some of such compounds as a tool to investigate the structure and function of the enzyme, in the treatment targeting COX-1 or detect
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Page/Page column 57
(2017/12/09)
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- METHODS OF INCREASING THE CYTOTOXICITY OF CHEMOTHERAPEUTIC AGENTS WITH MULTISUBSTRATE INHIBITORS OF HISTONE, PROTEIN-LYS, POLYAMINE ACETYLATION, AND POLYAMINE METABOLISM
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A method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of the HAT inhibitor of the following formula: wherein R is chosen from coenzyme A, (CH2)2NHCO(CH2)2NHCOR2; (CH2)2NHCOR3; (CH2)2NHCO(CH2)2NHCOR4; R1 is H, NH2, NH, N, and R1 can optionally cyclize with at least one other X2 to form a C3-8 membered ring containing C, O, S, or N; R2 is chosen from alkyl, cycloalkyl, aryl, heteroaryl; R3 is chosen from an alkyl, cycloalkyl, aryl, heteroaryl; R4 is chosen from CH(OH)C(CH3)2CH2)OCOR2; X1 is chosen from H or can cyclize with one other X2 or R1 to form a C3-8 membered ring containing C, O, S, or N; and X2 is chosen from C, N, NH, and can optionally cyclize with at least one other X2 or R1 to form a C3-8 membered ring containing C, O, S, or N; or a pharmaceutically acceptable salt or hydrate thereof, thereby treating the cancer.
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Page/Page column 21
(2016/09/26)
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- Synthesis of bifunctional biscatecholamine chelators for uranium decorporation
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New 1,3-dicarbonyl biscatecholamide ligands were synthesized to decorporate uranium for nuclear contamination. The derivatives were characterized via1H NMR spectroscopy,13C NMR spectroscopy, FTIR spectroscopy and mass spectrometry. The complexation abilities of ligands 8a–8d with UO22+, Cu2+and Zn2+were determined through spectrophotometric and potentiometric titrations technology. The antioxidant capacities of the ligands were assessed through DPPH antioxidant assay. Results indicated that ligands 8a–8d are potential decorporating agents for uranyl ion (pUO2up to 22.41) and copper(II) ion (pCu up to 17.71) without depletion of the essential element zinc (pZn lower than 7.48).
- Lei, Shan,Jin, Bo,Zhang, Qingchun,Zhang, Zhichao,Wang, Xiaofang,Peng, Rufang,Chu, Shijin
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p. 387 - 395
(2016/10/13)
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- Nanoformulations of anticancer thiosemicarbazones to reduce methemoglobin formation and improve anticancer activity
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Triapine is a promising anticancer thiosemicarbazone which was investigated in multiple clinical trials, where it was active against leukemia but not against solid cancers. This is probably based on insufficient drug levels in the tumor due to a short plasma half-life. Therefore, we encapsulated Triapine into polymeric nanoparticles and remote-loaded liposomes to improve the drug pharmacokinetics as well as targeted delivery. However, burst release of Triapine from both nanoformulations was observed, making the synthesis of two novel Triapine derivatives necessary in order to improve the remote-loading properties. Indeed, the encapsulation efficiency increased and for one derivative also the desired continuous drug release was in line with a strongly reduced cytotoxic activity against cancer cells. In vivo studies of this most promising formulation demonstrated a significant increase in survival of the animals compared to the free drug. Finally, we investigated drug-induced methemoglobin formation, a frequently observed side effect of thiosemicarbazones, which was completely prevented by the liposomal formulation.
- Fischer, Britta,Kryeziu, Kushtrim,Kallus, Sebastian,Heffeter, Petra,Berger, Walter,Kowol, Christian R.,Keppler, Bernhard K.
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p. 55848 - 55859
(2016/07/06)
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- FUNCTIONALIZED LINEAR LIGANDS AND COMPLEXES THEREOF
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The invention relates to chemical compounds and complexes that can be used in therapeutic and diagnostic applications.
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-
Paragraph 00251; 00254; 00255
(2016/07/27)
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- Isoxazole-Based-Scaffold Inhibitors Targeting Cyclooxygenases (COXs)
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A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates and
- Perrone, Maria Grazia,Vitale, Paola,Panella, Andrea,Ferorelli, Savina,Contino, Marialessandra,Scilimati, Antonio,Lavecchia, Antonio
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p. 1172 - 1187
(2016/07/13)
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- Isoxazole-based-scaffold inhibitors targeting cyclooxygenases (COXs)
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DMA new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline, two moieties typical of efflux pump substrates a
- Perrone, Maria Grazia,Vitale, Paola,Panella, Andrea,Ferorelli, Savina,Contino, Marialessandra,Lavecchia, Antonio,Scilimati, Antonio
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p. 1172 - 1187
(2017/10/13)
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- COMPOUND FOR TREATING CLOSTRIDIUM DIFFICILE
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The invention relates to compounds, compositions and polymers comprising a first component adapted to promote germination of Clostridium difficile (C.diff) and a second component which acts as an antimicrobial agent. Said compounds, compositions and polymers are useful for destroying C.diff where conventional antimicrobial agents are unsuccessful. The compositions can be formulated as coating or materials which actively destroy C.diff which come into contact with it. The germination promotion is induced by bile salts. The invention also relates to the use of such materials as a treatment for C.diff associated diseases and toxic megacolon.
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Page/Page column 72
(2016/06/14)
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- Preparation of N-Substituted N-Arylsulfonylglycines and Their Use in Peptoid Synthesis
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To increase the chemical diversity accessible with peptoids and peptide-peptoid hybrids, N-alkylated arylsulfonamides were used to prepare side chain protected N-substituted glycines compatible with solid-phase synthesis. The described procedures give acc
- Jobin, Steve,Vézina-Dawod, Simon,Herby, Claire,Derson, Antoine,Biron, Eric
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supporting information
p. 5626 - 5629
(2015/12/01)
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- PHARMACEUTICAL OR COSMETIC COMPOSITION FOR TREATING ALOPECIA
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The present invention relates to a cosmetic or pharmaceutical composition for treating alopecia, and in general for counteracting excessive hair loss, comprising as an active ingredient a compound of formula (I) R—N1-spermidine, or 1,4-butane-diamine,N-(3-aminopropyl)-N1—R. The compounds of general formula (I) are active in accordance with the objects of the present invention, and also sufficiently stable to allow effective application for topical use on the scalp without potentially being transformed into a different substance, which is no longer active, as a result of oxidation.
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-
Paragraph 0027
(2015/07/27)
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- Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives
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A structure-activity relationship study on polyamine derivatives led to the synthesis and the determination of antikinetoplastid activity of 17 compounds. Among them, a spermidine derivative (compound 13) was specifically active in vitro against Leishmania donovani axenic amastigotes (IC50 at 5.4 ??M; Selectivity Index >18.5) and a spermine derivative (compound 28) specifically active against Trypanosoma brucei gambiense (IC50 at 1.9 ??M; Selectivity Index >52).
- Jagu, Elodie,Djilali, Rachid,Pomel, S??bastien,Ramiandrasoa, Florence,Pethe, St??phanie,Labru?¤re, Rapha??l,Loiseau, Philippe M.,Blonski, Casimir
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p. 207 - 209
(2015/03/05)
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- Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives
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A structure-activity relationship study on polyamine derivatives led to the synthesis and the determination of antikinetoplastid activity of 17 compounds. Among them, a spermidine derivative (compound 13) was specifically active in vitro against Leishmania donovani axenic amastigotes (IC50 at 5.4 μM; Selectivity Index >18.5) and a spermine derivative (compound 28) specifically active against Trypanosoma brucei gambiense (IC50 at 1.9 μM; Selectivity Index >52).
- Jagu, Elodie,Djilali, Rachid,Pomel, Sébastien,Ramiandrasoa, Florence,Pethe, Stéphanie,Labruère, Rapha?l,Loiseau, Philippe M.,Blonski, Casimir
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p. 207 - 209
(2015/04/14)
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- Concise synthesis of spergualin-inspired molecules with broad-spectrum antibiotic activity
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There is a growing need to identify new, broad-spectrum antibiotics. The natural product spergualin was previously shown to have promising anti-bacterial activity and a privileged structure, but its challenging synthesis had limited further exploration. For example, syntheses of spergualin and its analogs have been reported in approximately 10 linear steps, with overall yields between 0.3 and 18%. Using the Ugi multi-component reaction, we assembled spergualin-inspired molecules in a single step, dramatically improving the overall yield (20% to 96%). Using this strategy, we generated 43 new analogs and tested them for anti-bacterial activity against two Gram-negative and four Gram-positive strains. We found that the most potent analogue, compound 6, had MIC values between 4 and 32 μg mL-1 against the six strains, which is a significant improvement on spergualin (MIC ~ 6.25 to 50 μg mL-1). These studies provide a concise route to a broad-spectrum antibiotic with a novel chemical scaffold. This journal is
- Assimon, Victoria A.,Shao, Hao,Garneau-Tsodikova, Sylvie,Gestwicki, Jason E.
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p. 912 - 918
(2015/05/27)
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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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- Synthesis of Actinomycetes natural products JBIR-94, JBIR-125, and related analogues
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The synthesis of the natural products JBIR-94, DCP, DFP, and CFP is reported. A strategy for the coupling of ferulic or coumaric acid to putrescine is described. We determined that EDCI was the most effective coupling agent for this synthesis. In addition amide coupling with saturated cinnamic acids derivatives provided the best yield. The synthesis of JBIR-125 is accomplished through a novel synthesis of differentially protected spermidine. Preliminary bioassay data demonstrated that all five compounds were active against Pseudomonas aeruginosa.
- Taj, Rafiq,Sorensen, John L.
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p. 7108 - 7111
(2015/12/01)
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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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- Synthetic development of new 3-(4-arylmethylamino)butyl-5-arylidene-rhodanines under microwave irradiation and their effects on tumor cell lines and against protein kinases
-
A new route to 3-(4-arylmethylamino)butyl-5-arylidene-2-thioxo-1,3-thiazolidine-4-one 9 was developed in six steps from commercial 1,4-diaminobutane 1 as starting material. The key step of this multi-step synthesis involved a solution phase "one-pot two-s
- Dago, Camille Dliko,Ambeu, Christelle N'ta,Coulibaly, Wacothon-Karime,Bkro, Yves-Alain,Mamyrbkova, Janat,Defontaine, Audrey,Baratte, Blandine,Bach, Stphane,Ruchaud, Sandrine,Le Guvel, Rmy,Ravache, Myriam,Corlu, Anne,Bazureau, Jean-Pierre
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p. 12412 - 12435
(2015/08/06)
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- Synthesis of DNA-Binding Peptoids
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Programmable molecular recognition through nucleic acid base pairing has enabled applications in nano- and biotechnology using DNA, RNA, PNA, and more recently, bifacial PNA (bPNA). We describe herein the synthesis and DNA recognition properties of peptoid backbones bearing the bifacial synthetic nucleobase melamine. These 'peptoid nucleic acids' hybridize with thymine-rich DNA, like their peptide cognate (bPNA). DNA complexation is highly sensitive to peptoid side-chain length and overall charge. Peptoids isomeric with peptide bPNA were less efficient at DNA recognition, possibly due to conformational and steric differences. 1 Triazines and DNA Molecular Recognition 2 Synthesis of DNA-Binding Peptoids 3 Peptoid-DNA Binding Studies
- Mao, Jie,Bong, Dennis
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supporting information
p. 1581 - 1585
(2015/06/30)
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- Flow-mediated synthesis of Boc, Fmoc, and Dd iv monoprotected diamines
-
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
-
supporting information
p. 422 - 425
(2015/03/03)
-
- Synthesis, Radiolabeling, and in Vivo Imaging of PEGylated High-Generation Polyester Dendrimers
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A fifth generation aliphatic polyester dendrimer was functionalized with vinyl groups at the periphery and a dipicolylamine Tc(I) chelate at the core. This structure was PEGylated with three different molecular weight mPEGs (mPEG160, mPEG350, and mPEG750) using thiol-ene click chemistry. The size of the resulting macromolecules was evaluated using dynamic light scattering, and it was found that the dendrimer functionalized with mPEG750 was molecularly dispersed in water, exhibiting a hydrodynamic diameter of 9.2 ± 2.1 nm. This PEGylated dendrimer was subsequently radiolabeled using [99mTc(CO)3(H2O)3]+ and purified to high (>99%) radiochemical purity. Imaging studies were initially performed on healthy rats to allow comparison to previous Tc-labeled dendrimers and then on xenograft murine tumor models, which collectively showed that the dendrimers circulated in the blood for an extended period of time (up to 24 h). Furthermore, the radiolabeled dendrimer accumulated in H520 xenograft tumors, which could be visualized by single-photon emission computed tomography (SPECT). The reported PEGylated aliphatic polyester dendrimers represent a new platform for developing tumor-targeted molecular imaging probes and therapeutics.
- McNelles, Stuart A.,Knight, Spencer D.,Janzen, Nancy,Valliant, John F.,Adronov, Alex
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p. 3033 - 3041
(2015/09/22)
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- PHARMACEUTICAL OR COSMETIC COMPOSITION FOR TREATING ALOPECIA
-
The present invention relates to a cosmetic or pharmaceutical composition for treating alopecia, and in general for counteracting excessive hair loss, comprising as an active ingredient a compound of formula (I) R-N1-spermidine, or 1,4-butanediamine,N-(3-aminopropyl)-N1-R. The compounds of general formula (I) are active in accordance with the objects of the present invention, and also sufficiently stable to allow effective application for topical use on the scalp without potentially being transformed into a different substance, which is no longer active, as a result of oxidation.
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Page/Page column 7
(2014/02/16)
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- Selective cleavage of carbamate protecting groups from aziridines with otera's catalyst
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Otera's distannoxane catalyst was found to promote the cleavage of carbamate groups from N-protected aziridines. This method enables the chemoselective cleavage of an aziridinyl N-carbobenzyloxy (Cbz) group in the presence of other N-Cbz groups. The selec
- Sun, Shan,Tirotta, Ilaria,Zia, Nicholas,Hutton, Craig A.
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p. 411 - 415
(2014/04/03)
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