- Homologation of polyamines in the rapid synthesis of lipospermine conjugates and related lipoplexes
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Lipopolyamine amides are useful cationic lipids, synthetic vectors for non-viral gene delivery. Desymmetrisation of readily available symmetrical polyamines is an important first step in the synthesis of such compounds. The application of trifluoroacetyl
- Geall, Andrew J.,Blagbrough, Ian S.
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- Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19
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In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.
- Wang, Siwen,Yang, Dazhou,Singh, Mandeep,Joo, Hyun,Rangel, Vanessa M.,Tran, Aaron,Phan, Erich,Xue, Liang
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- DNA condensation by cholesterol polyamine carbamates: A first step in gene therapy
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Novel cholesterol polyamine carbamates were prepared and their pKa values determined potentiometrically. Using the Henderson-Hasselbach equation, their charge, at physiological pH, was determined. Binding affinity for calf thymus DNA was measured using an
- Geall, Andrew J.,Blagbrough, Ian S.
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- Spermine-functionalized pen lene bisimide dyes-highly fluorescent bola-amphiphiles in water
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A series of four sperminefunctionalized perylene bisimide dyes without linkers (1) and with linkers (24) between the chromophore and the polyamine was synthesized. Protonation of the spermine moieties resulted in the formation of highly water-soluble dyes with up to six positively charged ammonium ions. The aggregation behavior of these strongly fluorescent bola-amphiphiles was studied in pure water as solvent by UV/Vis and fluorescence spectroscopy, and an astonishingly high fluorescence quantum yield of up to φfl=0.90 was observed for PBI 1. Atomic force microscopy and transmission electron microscopy were applied for the visualization of the aggregates on surfaces. Molecular modeling studies were performed by force-field calculations to explore the aggregate morphologies, which also provided valuable information on the influence of the additional alkylcarbonyl linkers. Our detailed spectroscopic and microscopic investigations revealed that the excellent optical properties of perylene bisimide chromophores can be used even in pure deionized water if their aggregation is efficiently suppressed.
- Rehm, Stefanie,Stepanenko, Vladimir,Zhang, Xin,Rehm, Thomas H.,Wuerthner, Frank
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- Evaluation method for polyamine uptake by N1-Dansylspermine
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Polyamine uptake by the polyamine transport system (PTS) in HTC cells was studied without the use of radioisotope-labeled polyamines. N-Dansylspermine (DNS343) was selected as a candidate probe to examine the PTS. DNS343 was incorporated into HTC cells, and its distribution in the cells was confirmed by fluorescence microscopy. The incorporation of DNS343 via PTS was confirmed by a competition study with bis(3-aminopropyl)amine, which is incorporated into cells via the PTS. In addition, the temperature dependency of DNS343 uptake and studies with inhibitors of ornithine decarboxylase and proteoglycan synthesis supported the use of DNS 343 as a fluorescent probe for the PTS. The kinetics studies for HTC cells treated with or without an ornithine decarboxylase inhibitor indicated that DNS343 uptake was saturable and that the apparent Km values for the PTS were approximately 1.5 μM in both types of cells at 37°C. Thus, we developed an assay method for the PTS by high-performance liquid-chromatography with DNS343. The inhibitory effect of polyamine analogs and related compounds on DNS343 uptake was then examined and discussed. Springer-Verlag 2009.
- Takao, Koichi,Sugita, Yoshiaki,Shirahata, Akira
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- Cheno-, urso- and deoxycholic acid spermine conjugates: Relative binding affinities for calf thymus DNA
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Cationic lipid polyamine amides (cholan-24-amides) have been prepared from chenodeoxycholic (3α,7α-dihydroxy), ursodeoxycholic (3α,7β- dihydroxy), and deoxycholic (3α,12α-dihydroxy) bile acids (5β-cholanes) by acylation of tri-Boc protected spermine. Their relative binding affinities for calf thymus DNA were determined using an ethidium bromide displacement assay. These lipopolyamine amides are synthetic vectors for non-viral gene delivery and models for lipoplex formation with respect to lipofection, a key first step in gene therapy. (C) 2000 Elsevier Science Ltd.
- Blagbrough, Ian S.,Al-Hadithi, Dima,Geall, Andrew J.
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- Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines
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We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH2-(CH2)3-NH-(CH2) 4-NH2] and norspermidine [NH2-(CH2)3-NH-(CH2) 3-NH2] backbones, with the N-alkyl group being held constant at C16 in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.
- Shrestha, Anurupa,Sil, Diptesh,Malladi, Subbalakshmi S.,Warshakoon, Hemamali J.,David, Sunil A.
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- A benzoperylene self-assembly complex with turn-on excimer emission for wash-free cell membrane fluorescence imaging
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A rational design of a benzoperylene probe BP-3 with positive charge allows for turn-on excimer emission, and wash-free cell membrane imaging. BP-3 possesses excellent chemical, thermal and photo stability. And the Stokes shift of the excimer emission is considerably large (90-100 nm), which very much avoids the background fluorescence interference.
- Niu, Niu,Zhou, Huipeng,Liu, Ning,Ren, Jia,Li, Weiqing,Yu, Cong
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- Synthesis of cholesterol-polyamine carbamates: PKa studies and condensation of calf thymus DNA
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Novel cholesterol-polyamine carbamates have been prepared and their pKas determined potentiometrically for conjugates substituted with up to five amino functional groups and the binding affinity for calf thymus DNA has also been determined; these polyamine carbamates are models for lipoplex formation with respect to gene delivery (lipofection), a key first step in gene therapy.
- Geall, Andrew J.,Taylor, Richard J.,Earll, Mark E.,Eaton, Michael A. W.,Blagbrough, Ian S.
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- Direct force measurement between cucurbit[6]uril and spermine using atomic force microscopy
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The rupture forces of individual host-guest complexes between surface-confined cucurbit[6]uril (CB[6]) and spermine derivatives were measured directly by atomic force microscopy (AFM). While 1,2-dithiolane-attached spermine was immobilized on a gold-coated AFM tip, perallyloxyCB[6] was attached to an allyl-terminated self-assembled monolayer on a gold substrate by olefin metathesis reaction. A histogram and autocorrelation function analysis yielded a rupture force of approximately 120 pN, which is the highest value ever reported for a synthetic host-guest system.
- Kim, Jeonghan,Kim, Youngkook,Baek, Kangkyun,Ko, Young Ho,Kim, Dongwoo,Kim, Kimoon
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- Synthesis and cellular studies of polyamine conjugates of a mercaptomethyl-carboranylporphyrin
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Seven polyamine conjugates of a tri(p-carboranylmethylthio) tetrafluorophenylporphyrin were prepared in high yields by sequential substitution of the p-phenyl fluoride of tetrakis(pentafluorophenyl)porphyrin (TPPF), and investigated as boron delivery agen
- Bhupathiraju, N.V.S. Dinesh K.,Vicente, M. Graca H.
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- Oligonucleotide-polyamine conjugates: Influence of length and position of 2′-attached polyamines on duplex stability and antisense effect
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Tethering cationic ligands to oligonucleotides results in zwitterionic molecules with often improved target affinity and better cell membrane permeation. Due to the ideal distance between cationic groups, polyamines are perfect counter ions for oligonucleotides. Using an easy and versatile procedure for attaching ligands to the 2′-position, polyamines were conjugated to distinct terminal and internal positions of oligonucleotides. With polyamines attached to terminal nucleosides, the affinity to complementary DNA or RNA strands increased with growing number of cationic amines. Tethering polyamines to an internal nucleoside of wild type DNA oligonucleotides resulted in a considerable decrease in duplex stability, but in phosphorothioates, no significant decrease was detected. Conjugates exhibited progressively higher target downregulation ability with increasing polyamine chain length in a human melanoma cell culture assay.
- Winkler, Johannes,Saadat, Karmin,Diaz-Gavilan, Monica,Urban, Ernst,Noe, Christian R.
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- Novel Polyamine-Naphthalene Diimide Conjugates Targeting Histone Deacetylases and DNA for Cancer Phenotype Reprogramming
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A series of hybrid compounds was designed to target histone deacetylases and ds-/G-quadruplex DNAs by merging structural features deriving from Scriptaid and compound 1. Compound 6 binds different DNA arrangements, inhibits HDACs both in vitro and in cells, and is able to induce a reduction of cell proliferation. Moreover, compound 6 displays cell phenotype-reprogramming properties since it prevents the epithelial to mesenchymal transition in cancer cells, inducing a less aggressive and migratory phenotype, which is one of the goals of present innovative strategies in cancer therapies.
- Pasini, Alice,Marchetti, Chiara,Sissi, Claudia,Cortesi, Marilisa,Giordano, Emanuele,Minarini, Anna,Milelli, Andrea
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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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- DNA condensation by bile acid conjugates of thermine and spermine
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DNA condensation was achieved with polyamine conjugates of bile acids. Spermine and thermine, linear tetraamines, were mono-acylated on a primary amine with cholic and lithocholic acids. The resulting polyamine amides were triamines containing either a propyl-butyl or a dipropyl spacing. Thus, the former mimics both the positive charge and its regiochemical distribution found in the natural product spermidine. Calf thymus DNA was extended by saturation with an intercalator, ethidium bromide. DNA binding affinity was then measured by fluorescence quenching with detection of residual intercalated ethidium bromide at 600 nm. The results obtained with this exclusion assay show that polyamine lithocholic acid conjugates condense DNA more efficiently than the analogous cholic acid polyamine amides.
- Blagbrough, Ian S.,Al-Hadithi, Dima,Geall, Andrew J.
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- A polyamine-modified near-infrared fluorescent probe for selective staining of live cancer cells
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We report the synthesis of novel polyamine-modified near-infrared (NIR) probes, which show excellent water-solubility and good optical properties. One probe was taken up efficiently by living cancer cell lines whereas no staining of the non-cancer cells was observed.
- K?nig, Sandra G.,?z, Simin,Kr?mer, Roland
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- A spermine-conjugated lipophilic Pt(iv) prodrug designed to eliminate cancer stem cells in ovarian cancer
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We developed a spermine-conjugated lipophilic Pt(iv) prodrug that is able to reduce the cancer stem cell population in ovarian cancer. The therapeutic effect is attributed to the hydrophobic tail and cationic spermine head group, the combination of which allows the Pt(iv) prodrug to localize in mitochondria and induce corresponding damage.
- Stilgenbauer, Morgan,Jayawardhana, Amarasooriya M. D. S.,Datta, Payel,Yue, Zhizhou,Gray, Michael,Nielsen, Frederick,Bowers, David J.,Xiao, Haihua,Zheng, Yao-Rong
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- Solid-phase synthesis of diamine and polyamine amino acid derivatives as HIV-1 Tat-TAR binding inhibitors
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A series of diamine and polyamine derivatives, either free amines or salts (HCl or TFA), of aspartic and glutamic acid were prepared in excellent yields using Rink Amide solid-phase synthesis. The asparagine and glutamine derivatives were all evaluated for their ability to inhibit Tat-TAR binding using a FIGS cellular assay, with the polyamine derivatives exhibiting the most promising binding activity.
- Bueno, G. Jimenez,Klimkait,Gilbert,Simons
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- Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: Design, synthesis, and validation
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Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μ. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.
- Corcé, Vincent,Morin, Emmanuelle,Guihéneuf, Solène,Renault, Eric,Renaud, Stéphanie,Cannie, Isabelle,Tripier, Rapha?l,Lima, Luís M. P.,Julienne, Karine,Gouin, Sébastien G.,Loréal, Olivier,Deniaud, David,Gaboriau, Fran?ois
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- Five-Component Self-Assembly of Cucurbituril-Based Hetero-pseudorotaxanes
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[5]Pseudorotaxanes can be obtained by self-sorting using heteroditopic guests and various cucurbituril homologues as hosts. The assembly and chemically induced disassembly of the pseudorotaxanes can be monitored by measuring the fluorescence of the anthracene guest in solution. Mass spectral evidence for the supramolecular assemblies is obtained in the gas phase. The disassembly in the gas phase can be achieved by collision-induced dissociation leading to the corresponding [2]- and [3]pseudorotaxanes.
- Carvalho, Cátia Parente,Domínguez, Zoe,Domínguez, Cristina,El-Sheshtawy, Hamdy S.,Silva, José Paulo Da,Arteaga, Jesús F.,Pischel, Uwe
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- Serum Compatible Spermine-Based Cationic Lipids with Nonidentical Hydrocarbon Tails Mediate High Transfection Efficiency
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Cationic lipids are widely used as nonviral synthetic vectors for gene delivery as a safer alternative to viral vectors. In this work, a library of L-shaped spermine-based cationic lipids with identical and nonidentical hydrophobic chains having variable carbon lengths (from C10 to C18) was designed and synthesized. These lipids were characterized and the structure-activity relationships of these compounds were determined for DNA binding and transfection ability when formulated as cationic liposomes. The liposomes were then used successfully for the transfection of HEK293T, HeLa, PC3, H460, HepG2, SH-SY5Y and Calu’3 cell lines. The transfection efficiency of lipids with nonidentical hydrocarbon chains was greater than the identical analogue. These reagents exhibited superior efficiency to the commercial reagent, Lipofectamine3000, under both serum-free and 10–40 % serum conditions in HEK293T, HeLa and H460 cell lines. The lipids were not toxic to the tested cell line. The results suggest that L-shaped spermine-based cationic lipids with nonidentical hydrocarbon tails could serve as efficient and safe nonviral vector gene carriers in further in vivo studies.
- Thongbamrer, Chopaka,Roobsoong, Wanlapa,Sattabongkot, Jetsumon,Opanasopit, Praneet,Yingyongnarongkul, Boon-ek
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- TPN10456, preparation method thereof and application of TPN10456 in medicine for treating multiple sclerosis
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The invention relates to a compound, a pharmaceutical application thereof, specifically relates to TPN10456, a preparation method of the TPN10456 and an application of the TPN10456 in a medicine for treating multiple sclerosis. The characteristics of the small molecular compound TPN10456 are disclosed in the invention. The invention relates to TPN10456 and application thereof in preparation of a medicine for treating multiple sclerosis.
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- Improved synthesis of the bifunctional chelator p-SCN-Bn-HOPO
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The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.4%. Herein we report an improved and efficient synthesis of p-SCN-Bn-HOPO in four steps with 14.3% overall yield which will improve its availability for further biological studies and wider application in PET imaging. The new synthetic route also allows variation in linker length and chemistries which may be helpful in modifying in vivo clearance behaviors of future agents.
- Bhupathiraju, N.V.S. Dinesh K.,Younes, Ali,Cao, Minhua,Ali, Jafar,Cicek, Huseyin T.,Tully, Kathryn M.,Ponnala, Shashikanth,Babich, John W.,Deri, Melissa A.,Lewis, Jason S.,Francesconi, Lynn C.,Drain, Charles Michael
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p. 6866 - 6871
(2019/07/22)
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- 8-polyamido dihydromyricetin derivative and preparation method and application thereof
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The present invention discloses an 8-polyamido dihydromyricetin derivative or a pharmaceutically acceptable hydrate and salt thereof including stereoisomers or tautomers thereof. The 8-polyamido dihydromyricetin derivative has anticancer activity and can be used for anticancer treatment drugs. The invention discloses a preparation method of the 8-polyamido dihydromyricetin derivative.
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Paragraph 0021; 0026
(2018/03/28)
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- COMPOSITIONS FOR THERAPEUTICS, TARGETED PET IMAGING AND METHODS OF THEIR USE
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Described herein is a chelator for radiolabels (e.g., 89Zr) for targeted PET imaging that is an alternative to DFO. In certain embodiments, the chelator for 89Zr is the ligand, 3,4,3-(LI-1,2- HOPO) ("HOPO"), which exhibits equal or superior stability compared to DFO in chemical and biological assays across a period of several days in vivo. As shown in FIG. 1, the HOPO is an octadentate chelator that stabilizes chelation of radiolabels (e.g., 89Zr). A bifunctional ligand comprising p-SCN-Bn-HOPO is shown in FIG. 4 and FIG. 5. Such a bifunctional ligand can eliminate (e.g., 89Zr) loss from the chelate in vivo and reduce uptake in bone and non-target tissue. Therefore, the bifunctional HOPO ligand can facilitate safer and improved PET imaging with radiolabeled antibodies.
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- SURFACE TREATMENTS
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Methods of treating surfaces to provide an antibacterial surface or a surface to which micro-dimensioned particles will adhere are disclosed. Water dispersible selenide-lipid and polycation-lipid constructs for use in the methods are also disclosed.
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Page/Page column 19; 20
(2016/12/07)
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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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- Light-triggered capture and release of DNA and proteins by host-guest binding and electrostatic interaction
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The development of an effective and general delivery method that can be applied to a large variety of structurally diverse biomolecules remains a bottleneck in modern drug therapy. Herein, we present a supramolecular system for the dynamic trapping and li
- Moratz, Johanna,Samanta, Avik,Voskuhl, Jens,Nalluri, Siva Krishna Mohan,Ravoo, Bart Jan
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supporting information
p. 3271 - 3277
(2015/03/05)
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- Hierarchically controlled protonation/aggregation of a porphyrin-spermine derivative
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We designed and synthesized a new porphyrin-spermine derivative that self-assembles under hierarchical control. Its aggregation processes depend on the protonation of both the spermine units and central core nitrogen atoms. Therefore, the time duration of
- Gangemi, Chiara Maria Antonietta,Randazzo, Rosalba,Fragalà, Maria Elena,Tomaselli, Gaetano Andrea,Ballistreri, Francesco Paolo,Pappalardo, Andrea,Toscano, Rosa Maria,Sfrazzetto, Giuseppe Trusso,Purrello, Roberto,D'Urso, Alessandro
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supporting information
p. 6722 - 6725
(2015/09/02)
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- Polyamine transport inhibitors: Design, synthesis, and combination therapies with difluoromethylornithine
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The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer cells. Several design features were discovered which strongly influenced PTI potency, sensitivity to amine oxidases, and cytotoxicity. These included changes in (a) the number of polyamine chains appended to the ring system, (b) the polyamine sequence, (c) the attachment linkage of the polyamine to the aryl core, and (d) the presence of a terminal N-methyl group. Of the series tested, the optimal design was N1,N1′,N1″-(benzene-1,3, 5-triyltris(methylene))tris(N4-(4-(methylamino)butyl)butane-1,4- diamine, 6b, which contained three N-methylhomospermidine motifs. This PTI exhibited decreased sensitivity to amine oxidases and low toxicity as well as high potency (EC50 = 1.4 μM) in inhibiting the uptake of spermidine (1 μM) in DFMO-treated L3.6pl human pancreatic cancer cells.
- Muth, Aaron,Madan, Meenu,Archer, Jennifer Julian,Ocampo, Nicolette,Rodriguez, Luis,Phanstiel, Otto
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p. 348 - 363
(2014/02/14)
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- Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation
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Ianthelliformisamines A-C are a novel class of bromotyrosine-derived antibacterial agents isolated recently from the marine sponge Suberea ianthelliformis. We have synthesized ianthelliformisamines A-C straightforwardly by the condensation of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic acid and the corresponding Boc-protected polyamine followed by Boc-deprotection with TFA. Further, using this reaction protocol, a library of their analogues (39 analogues) has been synthesized by employing 3-phenylacrylic acid derivatives and Boc-protected polyamine chains through various combinations of these two fragments differing in phenyl ring substitution, double bond geometry or chain length of the central spacer of the polyamine chain (shown in red color). All the synthesized compounds (ianthelliformisamines A-C and their analogues) were screened for antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. All synthetic analogues of ianthelliformisamine A showed bacterial growth inhibition against both strains (Escherichia coli and Staphylococcus aureus), having MIC values in the range of 117.8-0.10 μM, while none of the synthetic analogues of ianthelliformisamine C as well as the parent compound showed any detectable antibacterial activity. Interestingly, some of the synthetic analogues of ianthelliformisamines A and B exerted a bactericidal effect against both E. coli and S. aureus strains, decreasing viable bacterial count by 99% at concentrations as low as 2 × MIC. This journal is the Partner Organisations 2014.
- Khan, Faiz Ahmed,Ahmad, Saeed,Kodipelli, Naveena,Shivange, Gururaj,Anindya, Roy
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p. 3847 - 3865
(2014/06/09)
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- Structure-activity relationship studies of N-methylated and N-hydroxylated spider polyamine toxins as inhibitors of ionotropic glutamate receptors
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Polyamine toxins from spiders and wasps are potent open-channel blockers of ionotropic glutamate (iGlu) receptors. It is well-established that secondary amino groups in the polyamine moiety of these toxins are key to both selectivity and potency at iGlu receptors, still some native spider polyamine toxins comprise both N-methyl and N-hydroxy functionalities. Here, we investigate the effect of both N-methylation and N-hydroxylation of spider polyamine toxins by the synthesis and biological evaluation of the naturally occurring N-methylated argiopinines and pseudoargiopinines I and II, N-hydroxylated Agel-489 and Agel-505, as well as N-methylated analogues of the NMDA and AMPA iGlu receptor subtype selective antagonists ArgTX-93 and ArgTX-48. Efficient synthetic strategies for the synthesis of target compounds were developed, and evaluation of biological activity at AMPA and NMDA receptors identified highly potent and in some cases very selective ligands.
- N?rager, Niels G.,Poulsen, Mette H.,Jensen, Anna G.,Jeppesen, Nanna S.,Kristensen, Anders S.,Str?mgaard, Kristian
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p. 4940 - 4949
(2014/07/07)
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- B-Z transition of (dA-T)n duplexes induced by a spermine porphyrin-conjugate via an intermediate DNA conformation
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The spermine conjugate of the cationic porphyrin ligand (1) selectively induced the B-Z transition of the [(dA-T)n]2 sequence at low salt concentrations. The [(dG-C)n]2 sequence was not transformed into the Z-form. The B-Z transition was induced via an intermediate DNA conformation, which was formed by the external binding and formation of an assembly of 1 onto B-DNA.
- Sasaki, Hideaki,Sasaki, Shigeki
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p. 9024 - 9026
(2013/09/24)
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- Hybrid assemblies based on a gadolinium-containing polyoxometalate and a cationic polymer with spermine side chains for enhanced mri contrast agents
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Supramolecular assembly: Spherical and stable hybrid assemblies based on a cationic polymer with spermine side chains and an anionic Gd3+- containing polyoxometalate cluster (GdW) are prepared by electrostatic interaction (see figure). The T1-weighted MRI performance of GdW is enhanced about three times in the assemblies; meanwhile, the assemblies show good biocompatibility, which enables them to be promising candidates for MRI contrast agents. Copyright
- Chai, Wenqiang,Wang, Shan,Zhao, Hang,Liu, Guifeng,Fischer, Karl,Li, Haolong,Wu, Lixin,Schmidt, Manfred
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p. 13317 - 13321
(2013/10/08)
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- Polyamine functionalized carbon nanotubes: Synthesis, characterization, cytotoxicity and siRNA binding
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In this work we have synthesized a new series of cationic carbon nanotubes (CNTs) for siRNA binding. Both single- and multi-walled CNTs have been modified by addition or amidation reaction with short linear polyamine chains including putrescine, spermidin
- Singh, Prabhpreet,Samori, Cristian,Toma, Francesca Maria,Bussy, Cyrill,Nunes, Antonio,Al-Jamal, Khuloud T.,Menard-Moyon, Cecilia,Prato, Maurizio,Kostarelos, Kostas,Bianco, Alberto
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p. 4850 - 4860
(2011/10/09)
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- Light-responsive capture and release of DNA in a ternary supramolecular complex
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The wavelength determines whether DNA is captured in a light-responsive ternary supramolecular complex or released (see scheme). The reversible binding of DNA is triggered by a photoisomerization, which switches the complex from a multivalent to a monoval
- Nalluri, Siva Krishna Mohan,Voskuhl, Jens,Bultema, Jelle B.,Boekema, Egbert J.,Ravoo, Bart Jan
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supporting information; experimental part
p. 9747 - 9751
(2011/12/05)
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- Synthesis and applications of polyamine amino acid residues: Improving the bioactivity of an analgesic neuropeptide, neurotensin
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Conjugated polyamines are potential carriers for biothera- peutics targeting the central nervous system. We describe an efficient synthesis of a polyamine-based amino acid, lysine-trimethylene(diNo-syl)-spermine(triBoc) with Dde or Fmoc orthogonal protect
- Zhang, Liuyin,Lee, Hee-Kyoung,Pruess, Timothy H.,White, H. Steve,Bulaj, Grzegorz
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supporting information; experimental part
p. 1514 - 1517
(2010/02/28)
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- Synthesis of conjugated spermine derivatives with 7-nitrobenzoxadiazole (NBD), rhodamine and bodipy as new fluorescent probes for the polyamine transport system
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The synthesis of a series of conjugated spermine derivatives with benzoxadiazole, phenylxanthene or bodipy fluorophores is described. These fluorescent probes were used to identify the activity of the polyamine transport system (PTS). N1-Methylspermine NBD conjugate 5 proved to have the optimal fluorescence characteristics and was used to show a selectivity for PTS-proficient CHO versus PTS-deficient CHO-MG cells. It can therefore be used as a tool for the selection of cells sensitive to cytotoxic compounds vectored through the PTS.
- Guminski, Yves,Grousseaud, Martial,Cugnasse, Sandrine,Brel, Viviane,Annereau, Jean-Philippe,Vispe, Stephane,Guilbaud, Nicolas,Barret, Jean-Marc,Bailly, Christian,Imbert, Thierry
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body text
p. 2474 - 2477
(2009/12/25)
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- Polyamines and their use as antibacterial and sensitizing agents
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Polyamines with varying chain-lengths were evaluated for antimicrobial activity in order to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact Gram negative bacterial membranes. The compounds were found to possess significant antimicrobial activity and mediated via permeabilization of bacterial membranes. Homologated spermine, bis-acylated with C8 or C9 chains was found to profoundly sensitize E. coli to hydrophobic antibiotics such as rifampicin.
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Page/Page column 15; 16
(2010/11/28)
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- 7-POLYAMINOALKYL(OXY)IMINOMETHYLCAMPTOTHECINS BEARING PROTECTIVE GROUPS
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Compounds are disclosed with the general formula (I) in which the groups are as defined in the description here below and characterized by the presence of polyamine substituents on the imine/oxime residue, such amine groups being in turn protected by suitable protective groups. Said compounds are endowed with potent topoisomerase I inhibiting activity and therefore are useful as medicaments for the treatment of tumours and viral and parasite infections.
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Page/Page column 7
(2008/06/13)
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- The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism
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Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus, tyrosine was replaced by either apolar, conformationally constrained, or bulky amino acids, whereas the acyl unit and the polyamine moiety were kept unchanged. Analogues with tertiary amide groups were prepared for the first time. Pentafluorophenyl esters were employed for amide bond formation, establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl- 4-isoxazoyl)propanoic acid receptors (AMPAR) expressed in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the α-NHCO group as a donor in hydrogen bonding.
- J?rgensen, Malene R.,Olsen, Christian A.,Mellor, Ian R.,Usherwood, Peter N. R.,Witt, Matthias,Franzyk, Henrik,Jaroszewski, Jerzy W.
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- High-affinity multivalent DNA binding by using low-molecular-weight dendrons
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(Chemical Equation Presented) Nine spermines are better than one: Compound C2 exhibits high-affinity, salt-independent DNA binding as a consequence of the spermine array on its surface. Comparison with smaller dendrons and model compounds indicates a clea
- Kostiainen, Mauri A.,Hardy, John G.,Smith, David K.
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p. 2556 - 2559
(2007/10/03)
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- A sequential high-yielding large-scale solution-method for synthesis of philanthotoxin analogues
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A general, improved procedure for rapid synthesis of philanthotoxin analogues, a pharmacologically important class of polyamine conjugates, is described. The solution-phase procedure is illustrated by gram-scale synthesis of philanthotoxins PhTX-343 and P
- Wellendorph, Petrine,Jaroszewski, Jerzy W.,Hansen, Steen Honore,Franzyk, Henrik
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p. 117 - 122
(2007/10/03)
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- Practical synthesis of unsymmetrical polyamine amides
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Desymmetrisation of readily available symmetrical polyamines is an important first step in the synthesis of many polyamine containing natural products. Likewise in the synthesis of polyamine amides which are potentially useful for gene delivery and as neuroprotectants, based upon channel blocking toxins found in certain wasp and spider venoms. The application of trifluoroacetyl as a protecting group allows unsymmetrical polyamine amides to be easily prepared on a gram scale.
- Blagbrough, Ian S.,Geall, Andrew J.
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p. 439 - 442
(2007/10/03)
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- Isolation, structure elucidation, and synthesis of novel hydroxylamine-containing polyamines from the venom of the Agelenopsis aperta spider
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Novel hydroxylamine-containing polyamines have been isolated from the venom of Agelenopsis aperta, a funnel-web spider found throughout the western United States. 1H and 13C NMR in concert with UV spectroscopy provided important stru
- Jasys, V. John,Kelbaugh, Paul B.,Nason, Deane M.,Phillips, Douglas,Rosnack, Kenneth J.,Saccomano, Nicholas A.,Stroh, Justin G.,Volkmann, Robert A.
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p. 6696 - 6704
(2007/10/02)
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