- Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule
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Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, phenols, and coumarins. Polyamines such as spermine, spermidine, and many synthetic congeners are described to constitute a novel class of CA inhibitors (CAIs), interacting with the different CA isozymes with efficiency from the low nanomolar to millimolar range. The main structure?activity relationship for these CAIs have been delineated: the length of the molecule, number of amine moieties, and their functionalization are the main parameters controlling activity. The X-ray crystal structure of the CA II?spermine adduct allowed understanding of the inhibition mechanism. Spermine anchors to the nonprotein zinc ligand through a network of hydrogen bonds. Its distal amine moiety makes hydrogen bonds with residues Thr200 and Pro201, which further stabilize the adduct. Spermine binds differently compared to sulfonamides, phenols, or coumarins, rendering possible to develop CAIs with a diverse inhibition mechanism, profile, and selectivity for various isoforms.
- Carta, Fabrizio,Temperini, Claudia,Innocenti, Alessio,Scozzafava, Andrea,Kaila, Kai,Supuran, Claudiu T.
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- N1,N12-diacyl spermines: SAR studies on non-viral lipopolyamine vectors for plasmid DNA and siRNA formulation
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Purpose: To study the efficiency of novel synthetic N1,N 12-diacyl spermines on DNA and siRNA binding, and to compare their transfection efficiency with viability in cell lines. Methods: Five long chain N1,N12-diacyl lipopolyamines: N1,N 12-[didecanoyl, dimyristoyl, dimyristoleoyl, distearoyl and dioleoyl]-1,12-diamino-4,9-diazadodecane were synthesized from the naturally occurring polyamine spermine. Their abilities to condense DNA and to form nanoparticles were characterized. Transfection efficiencies were studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with N4,N9-regioisomers. Also, the abilities of these novel compounds to bind to siRNA-forming nanoparticles were studied using a RiboGreen intercalation assay, and their abilities to deliver fluorescein-tagged siRNA into cells were quantified and compared with TransIT-TKO. Results: By incorporating two long aliphatic chains and varying their acylation position, length, and oxidation state in a stepwise manner, we show efficient p and siRNA formulation and delivery to primary skin and cancer cell lines. Although two C14 chains (both saturated or both mono-cis-unsaturated) were efficient transfecting agents, they were highly toxic. Conclusions: N1,N 12-Dioleoyl spermine efficiently binds to and delivers pDNA and siRNA with high cell viability even in a primary skin cell line. It is a novel, efficient non-viral vector in the presence of serum.
- Ghonaim, Hassan M.,Li, Shi,Blagbrough, Ian S.
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- Lipopolysaccharide sequestrants: Structural correlates of activity and toxicity in novel acylhomospermines
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Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C16 for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED50 of 1.37 μM. Nitric oxide production in murine J774A.1 cells, as well as TNF-α in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to D-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.
- Miller, Kelly A.,Kumar, E.V.K. Suresh,Wood, Stewart J.,Cromer, Jens R.,Datta, Apurba,David, Sunil A.
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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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- 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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- Mild and efficient synthesis of N1,N5,N 10-tri-tert-butoxycarbonyl spermine
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This article describes a mild and efficient synthesis of N 1,N5,N10-tri-tert-butoxycarbonyl spermine from putrescine, with a 41% overall yield. The key steps include a Michael addition and Raney nickel (W-2) reduction. The advantages of this synthesis include a simple procedure, mild conditions, and good yields. Taylor & Francis Group, LLC.
- Feng, Xiangjun,Xia, Wenpin,Luo, Yu,Lu, Wei
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experimental part
p. 274 - 278
(2011/10/31)
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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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supporting information; experimental part
p. 4850 - 4860
(2011/10/09)
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- Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities
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A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory ac
- Verlinden, Bianca K.,Niemand, Jandeli,Snyman, Janette,Sharma, Shiv K.,Beattie, Ross J.,Woster, Patrick M.,Birkholtz, Lyn-Marie
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scheme or table
p. 6624 - 6633
(2011/12/01)
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- (Bis)urea and (Bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators
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The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 overexpression is thought to contribute to the development of cancer. W
- Sharma, Shiv K.,Wu, Yu,Steinbergs, Nora,Crowley, Michael L.,Hanson, Allison S.,Casero, Robert A.,Woster, Patrick M.
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scheme or table
p. 5197 - 5212
(2010/09/09)
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- CATIONIC LIPIDS AND USES THEREOF
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Cationic lipids, cationic lipid based drug delivery systems, ways to make them and methods of treating diseases using them are disclosed.
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Page/Page column 86
(2009/12/02)
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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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supporting information; scheme or table
p. 2478 - 2481
(2009/12/25)
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- NEW ADJUVANT
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The present invention provides a novel adjuvant for polynucleotide vaccines, and in particular the present invention provides immunogenic compositions comprising a polynucleotide encoding an antigen capable of eliciting an immune response and an adjuvant
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Page/Page column 32
(2010/11/25)
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- Lipophilic pyrylium salts in the synthesis of efficient pyridinium-based cationic lipids, gemini surfactants, and lipophilic oligomers for gene delivery
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Several new classes of pyridinium cationic lipids were synthesized and tested as gene delivery agents. They were obtained through a procedure that generates simultaneously the heterocyclic ring and the positively charged nitrogen atom, using lipophilic pyrylium salts as key intermediates that react with primary amines, yielding pyridinium salts. The choice of the appropriately substituted primary amine, diamine or polyamine, allows the design of the shape of the final lipids, gemini surfactants, or lipophilic polycations. We report also a comprehensive structure-activity relationship study that identified the most efficient structural variables at the levels of the hydrophobic anchor, linker, and counterion for these classes of pyridinium cationic lipids. This study was also aimed at finding the best liposomal formulation for the new transfection agents.
- Ilies, Marc Antoniu,Seitz, William A.,Johnson, Betty H.,Ezell, Edward L.,Miller, Aaron L.,Thompson, E. Brad,Balaban, Alexandru T.
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p. 3872 - 3887
(2007/10/03)
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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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- 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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- 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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- Synthesis and biological evaluation of s-triazine substituted polyamines as potential new anti-Trypanosomal drugs
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The P2 transporter is a nucleoside transporter which is unique to the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis. The transporter has been shown to bind some structural motifs not recognized by other tran
- Klenke,Stewart,Barrett,Brun,Gilbert
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p. 3440 - 3452
(2007/10/03)
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- Novel spermine-based cationic gemini surfactants for gene delivery
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Two types of spermine-based gemini surfactants have been synthesised; structure-activity studies have shown one type to be far superior in gene transection than the other.
- Ronsin,Perrin,Guedat,Kremer,Camilleri,Kirby
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p. 2234 - 2235
(2007/10/03)
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- Solid-phase synthesis of Agel 416; a novel approach to modified polyamines
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The synthesis of Agel 416, an acylpolyamine derived from the Spider Agenolopsis aperta, has been achieved on solid support. Stepwise synthesis of the polyamine chain was accomplished using N-protected amino alcohols and the Fukuyama-Mitsunobu reaction. (C) 2000 Published by Elsevier Science Ltd.
- Hone,Payne
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p. 6149 - 6152
(2007/10/03)
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- Solid-phase synthesis of symmetrical and unsymmetrical polyamine analogues of philanthotoxins using a Dde-linker
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The efficient construction of symmetrical and unsymmetrical polyamine analogues of philanthotoxins has been accomplished using the new Dde based linker. The linker allows the selective attachment of primary amines and the resulting linkage displays excell
- Chhabra, Siri Ram,Khan, Azra N.,Bycroft, Barrie W.
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p. 1095 - 1098
(2007/10/03)
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- Sinulamide: An H,K-ATPase inhibitor from a soft coral Sinularia sp.
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Sinulamide (1), a new tetraprenylated spermine derivative, has been isolated from a soft coral Sinularia sp. as an H,K-ATPase inhibitor. The structure was assigned on the basis of spectroscopic data and confirmed by a total synthesis.
- Sata, Noriko U.,Sugano, Michihiro,Matsunaga, Shigeki,Fusetani, Nobuhiro
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p. 719 - 722
(2007/10/03)
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- Macrocyclic polyamine lactam synthesis by diphenyl ether closure of 23-, 24- And 28-membered rings
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Novel 23-, 24- and 28-membered cyclic polyamine amides (cinnamamides) have been prepared by closure of diphenyl ethers; functionalized conjugates of spermidine and spermine underwent intramolecular aromatic nucleophilic substitution to afford nitro-substituted analogues of cadabicine class (24-membered polyamine lactam) alkaloids.
- Carrington, Simon,Fairlamb, Alan H.,Blagbrough, Lan S.
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p. 2335 - 2336
(2007/10/03)
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- Polyamine derivatives as inhibitors of trypanothione reductase and assessment of their trypanocidal activities
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Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the andoxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with K(i) values of 3.5, 5.5 and 9.5 μM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 μM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique gathway in Trypanosomatidae have potential as antitrypanosomal agents.
- O'Sullivan, Mary C.,Zhou, Qibing,Li, Zhili,Durham, Timothy B.,Rattendi, Donna,Lane, Schennella,Bacchi, Cyrus J.
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p. 2145 - 2155
(2007/10/03)
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