- Hydrophobic myristic acid modified PAMAM dendrimers augment the delivery of tamoxifen to breast cancer cells
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In the present study, cationic generation 5 polyamido amine (G5 PAMAM) dendrimers were hydrophobically modified by grafting the surface with lipid-like myristic acid (My) tails to augment their potential as a drug delivery vector in vitro. Nuclear magnetic resonance (1H NMR) measurements confirmed the presence of myristic acid tails at the dendrimer periphery (My-g-G5). Tamoxifen (TAM) an estrogen agonist, was entrapped in the My-g-G5 domains to impart them with anticancer properties. Transmission electron microscopy (TEM) observations indicate these My-g-G5/TAM complexes to be around 6-8 nm in size. Further, in vitro drug release studies ascertained the ability of My-g-G5/TAM complexes to release TAM in a sustained fashion under acidic conditions (pH 5.5). Cellular uptake studies revealed lysosomes as the target organelles of these nanocomplexes. MTT assay suggested good cell viability of My-g-G5 dendrimers and strong inhibitory effects of My-g-G5/TAM complexes in MCF-7 (human breast adenocarcinoma, estrogen receptor (ER) positive) cells. Dual fluorescence staining, reactive oxygen species (ROS) generation, cell cycle analysis, field emission scanning electron microscopy (FE-SEM), change in mitochondrial membrane potential (MMP, ΔΨ) and gene expression studies revealed the apoptosis-inducing ability of My-g-G5/TAM in MCF-7 cells. Based on our findings, we present these hydrophobically modified G5 PAMAM dendrimers as prospective nanocarriers for TAM delivery for anticancer applications.
- Matai, Ishita,Gopinath
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Read Online
- A METHOD FOR MODIFICATION OF PEPTIDES IMMOBILIZED ON A SOLID SUPPORT BY TRACELESS REDUCTIVELY CLEAVABLE LINKER MOLECULES
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The present invention relates to a method for modifying and purifying peptides comprising an immobilizing step, a modification step and a releasing step. In the immobilizing step, a crude linker-tagged peptide L-P is coupled to a solid support yielding an immobilized linker-tagged peptide S-L-P. Subsequently, the immobilized linker-tagged peptide S-L-P is modified with one or more organic molecules yielding an immobilized linker-tagged peptide S-L-mP. Finally, the modified peptide is released via a reduced intermediate RI. The linker molecule is a compound of formula 1, X-Tbb-Vaa-U-Y-Z (1), which can be coupled to a purification resin via the moiety X and to a peptide via the moiety Y under the release of the leaving group Z. T is an optional spacer moiety and V is an optional electron withdrawing moiety. U is an aryl or 5- or 6-membered heteroaryl moiety bound to at least one electron withdrawing moiety V, W or E. The linker is stable under acidic conditions and releases the peptide upon addition of a reducing agent.
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Page/Page column 57; 58
(2021/02/12)
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- Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis
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Lipid metabolism in Mycobacterium tuberculosis (Mtb) relies on 34 fatty acid adenylating enzymes (FadDs) that can be grouped into two classes: fatty acyl-CoA ligases (FACLs) involved in lipid and cholesterol catabolism and long chain fatty acyl-AMP ligases (FAALs) involved in biosynthesis of the numerous essential and virulence-conferring lipids found in Mtb. The precise biochemical roles of many FACLs remain poorly characterized while the functionally non-redundant FAALs are much better understood. Here we describe the systematic investigation of 5′-O-[N-(alkanoyl)sulfamoyl]adenosine (alkanoyl adenosine monosulfamate, alkanoyl-AMS) analogs as potential multitarget FadD inhibitors for their antitubercular activity and biochemical selectivity towards representative FAAL and FACL enzymes. We identified several potent compounds including 12-azidododecanoyl-AMS 28, 11-phenoxyundecanoyl-AMS 32, and nonyloxyacetyl-AMS 36 with minimum inhibitory concentrations (MICs) against M. tuberculosis ranging from 0.098 to 3.13 μM. Compound 32 was notable for its impressive biochemical selectivity against FAAL28 (apparent Ki = 0.7 μM) versus FACL19 (Ki > 100 μM), and uniform activity against a panel of multidrug and extensively drug-resistant TB strains with MICs ranging from 3.13 to 12.5 μM in minimal (GAST) and rich (7H9) media. The SAR analysis provided valuable insights for further optimization of 32 and also identified limitations to overcome.
- Aldrich, Courtney C.,Baran, Marzena,Boshoff, Helena I. M.,Fu, Peng,Grimes, Kimberly D.,Sibbald, Paul A.,Wilson, Daniel J.
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- MODIFIED RELAXIN POLYPEPTIDES COMPRISING A PHARMACOKINETIC ENHANCER AND USES THEREOF
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The present disclosure generally relates to modified relaxin polypeptides, such as modified human relaxin 2 polypeptides, comprising a non-naturally encoded amino acid which is linked to a pharmacokinetic enhancer, and therapeutic uses of such polypeptides, such as for the treatment of cardiovascular conditions (such as heart failure) and/or conditions relating to fibrosis.
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Paragraph 0395-0396
(2018/08/25)
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- Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymer and Their Nanomicelles for Nonviral Gene Delivery Applications
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The aim of this study was to synthesize and characterize fatty acid-grafted-chitosan (fatty acid-g-CS) polymer and their nanomicelles for use as carriers for gene delivery. CS was hydrophobically modified using saturated fatty acids of increasing fatty acyl chain length. Carbodiimide along with N-hydroxysuccinimide was used for coupling carboxyl group of fatty acids with amine groups of CS. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to quantify fatty acyl substitution onto CS backbone. The molecular weight distribution of the synthesized polymers was determined using size exclusion high performance liquid chromatography and was found to be in range of the parent CS polymer (～50 kDa). The critical micelle concentration (cmc) of the polymers was determined using pyrene as a fluorescent probe. The cmc was found to decrease with an increase in fatty acyl chain length. The amphiphilic fatty acid-g-CS polymers self-assembled in an aqueous environment to form nanomicelles of ～200 nm particle size and slightly positive net charge due to the cationic nature of free primary amino groups on CS molecule. These polymeric nanomicelles exhibited excellent hemo- and cytocompatibility, as evaluated by in vitro hemolysis and MTT cell viability assay, respectively, and showed superior transfection efficiency compared to unmodified chitosan and naked DNA. The surface of these nanomicelles can be further modified with ligands allowing for selective targeting, enhanced cell binding, and internalization. These nanomicelles can thus be exploited as potential nonviral gene delivery vectors for safe and efficient gene therapy.
- Sharma, Divya,Singh, Jagdish
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p. 2772 - 2783
(2017/11/20)
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- Single-stranded nucleic acid molecule for regulating expression of gene having delivering function
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The invention provides a single-stranded nucleic acid capable of inhibiting expression of a target gene having a delivery function. The nucleic acid contains, from the 5′-side to the 3′-side, a 5′-side region (Xc), a linker region (Lx), an inner region (Z), a linker region (Ly) and a 3′-side region (Yc) in this order, wherein the inner region (Z) is constituted by linkage of the inner 5′-side region (X) and the inner 3′-side region (Y), the 5′-side region (Xc) is complementary to the inner 5′-side region (X), the 3′-side region (Yc) is complementary to the inner 3′-side region (Y), at least one of the inner region (Z), the 5′-side region (Xc) and the 3′-side region (Yc) comprises an expression inhibitory sequence that inhibits expression of a target gene, and at least one of the 5′-terminus, the 3′-terminus, the linker region (Lx) and the linker region (Ly) is bound to a bio-related substance.
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Page/Page column 41
(2017/06/19)
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- KRN7000 analogue with antitumor activity and synthetic method thereof
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The invention provides a KRN7000 analogue with antitumor activity and a synthetic method thereof, wherein the KRN7000 analogue is synthesized by substituting oxygen atoms with sulfur atoms in a galactose sugar ring, and replacing various substituting groups at positions R1 and R2, so that a method for obtaining KRN7000 analogues with better anticancer and antitumor bioactivities and other bioactivities is provided. The method is characterized by comprising the steps as shown in the specification.
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Paragraph 0024; 0025
(2016/11/02)
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- A systematic understanding of gelation self-assembly: solvophobically assisted supramolecular gelation via conformational reorientation across amide functionality on a hydrophobically modulated dipeptide based ambidextrous gelator, N-n-acyl-(l)Val-X(OBn), (X = 1,ω-amino acid)
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A systematic investigation on gelation self-assembly has been performed on a hydrophobically modulated dipeptide based ambidextrous gelator, N-n-acyl-(l)Val-X(OBn), (X = 1,ω-amino acid). To elucidate the effect of hydrophobic tuning on gelator architecture towards its gelation self-assembly, three sets of gelators with a common formula: CmH2m+1C(=O)NH(l)Val(C=O)NH-(CH2)n-(C=O)OBn, were synthesized, Set-I includes gelators with n = 2, m = 9, 11, 13, 15, 17, for Set-II it is n = 2, 3, 5, m = 13 and Set-III comprises of two isomeric gelators (n = 2, m = 15; n = 10, m = 7). Gelation has been critically analyzed in various apolar (aromatic and aliphatic) and polar (protic and aprotic) solvents using FESEM, CD, IR, WAXRD and rheological studies. Obtained results reveal that π-π type interaction dictates the primary molecular alignment and positioning of amide functionality across the aliphatic chain which influences the peptidic orientation in parallel (when m > n) or antiparallel (when m gel and yield stress of gel systems increases with m, but for a given m, the trend goes apparently inverse with the increasing n. Circular dichroism (CD) studies suggest an intriguing evidence of non-planarity of amide plane during self-assembly, highlighting the involvement of conformational change taking place during molecular organization towards its gelation. Despite complex nature of solvent-gelator interaction, the effect of H-bonding component of solubility parameters was found to have a significant role on self-assembly. Overall, supramolecular forces acting at specific functionalities encrypted in gelator backbone must overcome the solvation energy with synergic assistance of solvophobic effect towards stabilization of gel-network with optimum gelator backbone conformation for achieving required enthalpic contribution for self-assembly.
- Haldar, Saubhik,Karmakar, Koninika
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p. 66339 - 66354
(2015/08/18)
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- Synthesis and biological activities of 5-thio-α-GALCERS
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NKT cells, a unique subset of T cells that recognizes glycolipid antigens presented by CD1d molecules, are believed to produce key cytokines of both Th1 and Th2 T cells and are thus involved in the control of several types of immune response. As an active glycolipid antigen having α-galactosyl ceramide core structure, KRN7000 showed promising immunostimulation activity and was selected as an anticancer drug candidate for further clinical application. In this report, three new KRN7000 structural analogues were designed and synthesized, in which the ring oxygen of the galactopyranose residue is replaced by a sulfur atom along with the variation on the lipid chain. Their abilities for stimulating mouse NKT cells to produce IFN-γ and IL-4 were evaluated both in vivo and in vitro.
- Bi, Jingjing,Wang, Jing,Zhou, Kai,Wang, Yuancheng,Fang, Min,Du, Yuguo
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supporting information
p. 476 - 480
(2015/04/27)
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- Partial synthesis of ganglioside and lysoganglioside lipoforms as internal standards for MS quantification
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Within recent years, ganglioside patterns have been increasingly analyzed by MS. However, internal standards for calibration are only available for gangliosides GM1, GM2, and GM3. For this reason, we prepared homologous internal standards bearing nonnatural fatty acids of the major mammalian brain gangliosides GM1, GD1a, GD1b, GT1b, and GQ1b, and of the tumor-associated gangliosides GM2 and GD2. The fatty acid moieties were incorporated after selective chemical or enzymatic deacylation of bovine brain gangliosides. For modifi cation of the sphingoid bases, we developed a new synthetic method based on olefi n cross metathesis. This method was used for the preparation of a lyso-GM1 and a lyso-GM2 standard. The total yield of this method was 8.7% for the synthesis of d17:1-lyso-GM1 from d20:1/18:0-GM1 in four steps. The title compounds are currently used as calibration substances for MS quantifi cation and are also suitable for functional studies.
- Gantner, Martin,Schwarzmann, Günter,Sandhoff, Konrad,Kolter, Thomas
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p. 2692 - 2704
(2015/02/19)
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- Systematic exploration of lipophilic tags that allow efficient anchoring of aptamers to live cell surfaces
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We carried out a systematic exploration of lipophilic tag molecules that allow efficient anchoring of aptamers to live cell surfaces. Among the lipids tested, the C16 dialkyl (dipalmitoylphosphatidylethanolamine) tag showed a good performance: a high anchoring yield and long retention on live cells. The 3'-C16 dialkyl tag-labeled fluorescent aptamer sensor, targeting thrombin, was prepared. The aptamer sensor was anchored successfully to live cells, allowing fluorescence detection of thrombin on the cell surface.
- Tokunaga, Takeshi,Kuwahata, Kohei,Sando, Shinsuke
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supporting information
p. 127 - 129
(2013/03/28)
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- Synthesis and physicochemical properties of new tripodal amphiphiles bearing fatty acids as a hydrophobic group
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Saturated fatty acids (FA) were grafted using tyrosine as a spacer group to the cyclotriphosphazene ring along with equimolar hydrophilic methoxy poly(ethylene glycol) (MPEG) in cis-nongeminal way. Seven new cyclotriphosphazene amphiphiles were prepared from combinations of hydrophilic MPEGs with different molecular weights of 350, 550, 750 and 1000 and four different fatty acids of different hydrophobicity including lauric, myristic, palmitic and stearic acids. These steric amphiphiles bearing fatty acids as a hydrophobic group were found to form more stable micelles with very low critical micelle concentrations (CMC) (2.95-7.80 mg/L) compared with oligopeptide analogues, and their highly hydrophobic core environment is unique and potentially useful for various biomedical applications.
- Avaji, Prakash G.,Jadhav, Vithal B.,Cui, Jin Xin,Jun, Yong Joo,Lee, Hwa Jeong,Sohn, Youn Soo
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supporting information
p. 1763 - 1767
(2013/04/10)
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- New parasite inhibitors encompassing novel conformationally-locked 5′-acyl sulfamoyl adenosines
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We describe the design, synthesis and biological evaluation of conformationally-locked 5′-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3′-endo, North-type) nucleosides have been synthesized by covalently attaching a 4′-CH2-O-2′ bridge (Fig. 2) across C2′-C4′ of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5′-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC50 = 0.25-0.51 μM. In particular, the potent 5′-pentanyl acyl sulfamoyl adenosine derivative 17 (IC50 = 0.25 μM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC50 >4 μM) and in diploid human fibroblasts MRC-5 cell lines (CC50 4 μM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5′ can modulate the toxicity of 5′-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.
- Dixit, Shailesh S.,Upadhayaya, Ram Shankar,Chattopadhyaya, Jyoti
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experimental part
p. 6121 - 6129
(2012/09/05)
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- Cell permeable ITAM constructs for the modulation of mediator release in mast cells
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Spleen tyrosine kinase (Syk) is essential for high affinity IgE receptor (FcεRI) mediated mast cell degranulation. Once FcεRI is stimulated, intracellular ITAM motifs of the receptor are diphosphorylated (dpITAM) and Syk is recruited to the receptor by binding of the Syk tandem SH2 domain to dpITAM, resulting in activation of Syk and, eventually, degranulation. To investigate intracellular effects of ITAM mimics, constructs were synthesized with ITAM mimics conjugated to different cell penetrating peptides, i.e. Tat, TP10, octa-Arg and K(Myr)KKK, or a lipophilic C12-chain. In most constructs the cargo and carrier were linked to each other through a disulfide bridge, which is convenient for combining different cargos with different carriers and has the advantage that the cargo and the carrier may be separated by reduction of the disulfide once it is intracellular. The ability of these ITAM constructs to label RBL-2H3 cells was assessed using flow cytometry. Fluorescence microscopy showed that the octa-Arg-SS-Flu-ITAM construct was present in various parts of the cells, although it was not homogeneously distributed. In addition, cell penetrating constructs without fluorescent labels were synthesized to examine degranulation in RBL-2H3 cells. Octa-Arg-SS-ITAM stimulated the mediator release up to 140%, indicating that ITAM mimics may have the ability to activate non-receptor bound Syk.
- Kuil, Joeri,Fischer, Marcel J. E.,De Mol, Nico J.,Liskamp, Rob M. J.
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experimental part
p. 820 - 833
(2011/04/22)
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- Functionalization of poly(amidoamine) dendrimers with hydrophobic chains for improved gene delivery in mesenchymal stem cells
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A new family of gene delivery vectors is synthesized consisting of a medium-size generation PAMAM dendrimer (generation 5, with amine termini) core randomly linked at the periphery to hydrophobic chains that vary in length (12 to 16 carbon alkyl chains) and number (from 4.2 to 9.7 in average). The idea subjacent to the present work is to join the advantages of the cationic nature of the dendrimer with the capacity of lipids to interact with biological membranes. Unlike other amphiphilic systems designed for the same purpose, where the hydrophobic and hydrophilic moieties coexist in opposite sides, the present vectors have a hydrophilic interior and a hydrophobic corona. The vectors are characterized in respect to their ability to neutralize, bind and compact plasmid DNA (pDNA). The complexes formed between the vectors and pDNA are analyzed concerning their size, ζ-potential, resistance to serum nucleases, capacity of being internalized by cells and transfection efficiency. These new vectors show a remarkable capacity for mediating the internalization of pDNA with minimum cytotoxicity, being this effect positively correlated with the -CH2- content present in the hydrophobic corona. Gene expression in MSCs, a cell type with relevancy in the regenerative medicine clinical context, is also enhanced using the new vectors but, in this case, the higher efficiency is shown by the vectors containing the smallest hydrophobic chains.
- Santos, José L.,Oliveira, Hugo,Pandita, Deepti,Rodrigues, Jo?o,Pêgo, Ana P.,Granja, Pedro L.,Tomás, Helena
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scheme or table
p. 55 - 64
(2011/10/31)
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- Synthetic libraries of tyrosine-derived bacterial metabolites
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The preparation of a collection of 131 small molecules, reminiscent of families of long chain N-acyl tyrosines, enamides and enol esters that have been isolated from heterologous expression of environmental DNA (eDNA) in Escherichia coli, is reported. The synthetic libraries of N-acyl tyrosines and their 3-keto counterparts were prepared via solid-phase routes, whereas the enamides and enol esters were synthesized in solution-phase.
- Georgiades, Savvas N.,Clardy, Jon
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supporting information; experimental part
p. 3117 - 3121
(2009/04/03)
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- Cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine-Based Inhibitors of Human N-Myristoyltransferase-1
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N-Myristoyltransferase (NMT) is an emerging therapeutic target that catalyzes the attachment of myristate to the N terminus of an acceptor protein. We have developed a medium-throughput assay for screening potential small molecule inhibitors of human NMT-1 consisting of recombinant enzyme, biotinylated peptide substrate, and [3H]myristoyl-CoA. Approximately 16,000 diverse compounds have been evaluated, and significant inhibition of NMT was found with 0.8% of the compounds. From these hits, we have identified the cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine (COPP) chemotype as inhibitory toward human NMT-1. Thirty-two compounds containing this substructure inhibited NMT-1, with IC50 values ranging from 6 μM to millimolar concentrations, and a quantitative structure-activity relationship equation (r2 = 0.72) was derived for the series. The most potent inhibitor (24, containing 9-ethyl-9H-carbazole) demonstrated competitive inhibition for the peptide-binding site of NMT-1 and noncompetitive inhibition for the myristoyl-CoA site. Computational docking studies using the crystal structure of the highly homologous yeast NMT confirmed that 24 binds with excellent complementarity to the peptide-binding site of the enzyme. To evaluate the ability of 24 to inhibit NMT activity in intact cells, monkey CV-1 cells expressing an N-myristoylated green fluorescent protein (GFP) fusion protein were treated with a known NMT inhibitor or with 24. Each compound caused the redistribution of GFP from the plasma membrane to the cytosol. Furthermore, 24 inhibits cancer cell proliferation at doses similar to those that inhibit protein myristoylation. Overall, these studies establish an efficient assay for screening for inhibitors of human NMT and identify a novel family of inhibitors that compete at the peptide-binding site and have activity in intact cells.
- French, Kevin J.,Zhuang, Yan,Schrecengost, Randy S.,Copper, Jean E.,Xia, Zuping,Smith, Charles D.
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p. 340 - 347
(2007/10/03)
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- Amphiphilic anionic analogues of galactosylceramide: Synthesis, anti-HIV-1 activity, and gp120 binding
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We describe the synthesis together with the results of anti-HIV-1 activity and gp120-monolayer binding experiments of new galactosyl amphiphiles, analogues of galactosylceramide, an alternative receptor used by HIV to infect CD4 negative cells. These compounds consist of single- and double-chain amphiphiles containing one or two galactose residues. To favor their clustering into galactosyl-rich microdomains, their molecular structure contains also an amino group or several hydroxyls or anionic groups, such as carboxylate, sulfate, sulfonate, and phosphate. Among the 12 new galactosylated compounds reported, a specific anti-HIV activity, although moderate (IC50 from 10 to 50 μM), was detected only for three of them, i.e., I-GalSer-[CO2Na][C14], II-GalSer[C14][C7SO3Na], and II-GalSer[C2SO4Na][C14], which contain an anionic group. The marked increase of surface pressure which was observed upon addition of gp120 into the aqueous subphase underneath the monolayers containing these galactolipids indicated gp120 insertion into the monolayers, suggesting that binding of these three derivatives to HIV-1 gp120 may be responsible for their anti-HIV activity.
- Faroux-Corlay,Greiner,Terreux,Cabrol-Bass,Aubertin,Vierling,Fantini
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p. 2188 - 2203
(2007/10/03)
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- Einfluss von Ankerlipiden auf die Homogenitaet und Mobilitaet von Lipiddoppelschichten auf traegerfixierten Polymerfilmen
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Keywords: Biomembranen; Fluoreszenz; Lipiddoppelschicht; Polymerfilme
- Beyer, Dierk,Elender, Gunther,Knoll, Wolfgang,Kuehner, Martin,Maus, Steffen,et al.
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p. 1791 - 1794
(2007/10/03)
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- Determination of N-terminal myristoylation of proteins using a combined gas chromatographic/mass spectrometric assay of derived myristoylglycine: Electron impact-induced fragmentation of acylglycine derivatives
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A method based on gas chromatography/mass spectrometry is described for the detection of N-terminal myristoylation of proteins. Myristoylglycine, derivatized as its trimethylsily (TMS) ester, gave an electron impact mass spectrum containing abundant molecular and [M - CH3]+ ions, together with several ions diagnostic of the acyl glycine moiety, namely at m/z 145, 158, 172 and 189. The compositions of these ions and the mechanism that produced them were investigated by high-resolution mass measurements, deuterium labelling and the preparation of analogons compounds. As these ions were present in the spectra of all acylglycines examined, they could be used as markers for these compounds. A selected-ion monitoring method for the detection of myristoylglycine was set up using the above ions and was used to confirm the presence of N-terminal myristoylation in three referenee peptides. A series of ions produced by radical-induced cleavage of the alkyl chain following TMS group migration and elimination of carbon dioxide gave information on the structure of the chain and could be used to determine the structure of other potential acylglycines such as those with unsaturated acyl chains. Thus the derivatives could be used not only to detect myristoylation of protein, but also to detect and determine the structures of other acyl substituents.
- McIlhinney,Harvey
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p. 900 - 910
(2007/10/02)
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- Synthesis of myristoyl CoA analogues and myristoyl peptides as inhibitors of myristoyl CoA:protein N-myristoyltransferase
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To develop inhibitors of myristoyl CoA:protein N-myristoyltransferase (NMT), a series of myristoyl coenzyme A analogues and myristoyl peptides were synthesized, including S-(2-oxopentadecyl)-CoA (1), S-(2-hydroxypentadecyl)- CoA (2), S-(2-oxopentadecyl)-pantetheine (3), Myr-N-Gly-(L)-Phe (4), Myr-N- Gly-(L)-Tyr (5), and Myr-N-Gly-(L)-Asn-Ala-Ala-Ser-Ala-Arg-(NH2) (6). Biological evaluation of these compounds in an in vitro NMT enzyme assay revealed that the nonhydrolyzable acyl CoA analogue 1 was the most potent inhibitor [inhibitor dissociation constant (K(i)) = 24 nM]. A preliminary structure-activity relationship study showed that the adenosine moiety and the 2-keto group in this nonhydrolyzable analogue were necessary for inhibitory activity. A possible mechanism for the inhibition of NMT by 1 was proposed, in which 1 might block the reaction at the stage of an acyl-CoA- NMT-peptide complex. Product analogues such as the myristoylated peptides 4- 6 were poor inhibitors of NMT.
- Zheng,Hu,Cassady,Paige,Geahlen
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p. 233 - 238
(2007/10/02)
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- SYNTHESIS AND BIOLOGICAL ACTIVITIES OF SOME PEPTIDOGLYCAN MONOMER DERIVATIVES
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N-acyl derivatives and N-acetyl-glucosaminyl-β-(1->4)-N-acetyl-muramoyl-L-alanyl-D-isoglutaminyl-L-meso-diaminopimelyl-(D-amide)-(L)-D-alanyl-D-alanine (peptidoglycan monomer, PGM) complexes with some bivalent metals were prepared and their immunomodulatory activities examined.
- Suskovic, B.,Vajtner, Z.,Naumski, R.
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p. 8407 - 8416
(2007/10/02)
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- Synthesis of the α-Methyl Ketoside of 5-Amino Neuraminic Acid Methyl Ester and Its Corresponding 5-Myristoyl and 5-Cyclopropanoyl Derivative
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This communication describes the first synthesis of the α-methyl ketoside of an N-unprotected neuraminic acid in the form of its methyl ester (Neu5NH21Me-α-2Me) (5a).This compound is a valuable intermediate for the synthesis of unnatural N-substituted sialic acids.Syntheses of Neu5myristoyl1Me-α-2Me (5b) and Neu5cyclopropanoyl1Me-α-2-Me (5c) are presented.
- Schrell, Andreas,Whitesides, George M.
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p. 1111 - 1114
(2007/10/02)
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- Synthesis and Biological Activities of N-Acetylglucosaminyl-&β(1->4)-N-Acetylmuramyl Tri- and Tetrapeptide Derivatives
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The acylated, amidated and esterified derivatives of N-acetylglucosaminyl-β(1->4)-N-acetylmuramyl tri- and tetrapeptide were synthesized and examined as to their protective effect on pseudomonal infection in the mouse and pyrogenicity in the rabbit.Modifications of the terminal end function of the peptide moieties in their molecules caused enhancement of resistance to pseudomonal infection and reduction of pyrogenicity.Among the compounds tested, sodium N-acetylglucosaminyl-β(1->4)-N-acetylmuramyl-L-alanyl-D-isoglutaminyl-(L)-stearoyl-(D)-meso-2,6-diaminopimelic acid-(D)-amide and sodium N-acetylglucosaminyl-β(1->4)-N-acetylmuramyl-L-alanyl-D-isoglutaminyl-(L)-stearoyl-(D)-meso-2,6-diaminopimelic acid-(D)-amide-(L)-D-alanine were found to be advantageous and conceivably worthwhile for further investigation as immunobiologically active compounds.
- Furuta, Rhyuji,Kawata, Shigeo,Naruto, Shunsuke,Minami, Akira,Kotani, Shozo
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p. 2561 - 2572
(2007/10/02)
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- Kasugamycin derivatives, pharmaceutical compositions and method of use
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This invention relates to new aminoglycoside derivatives and pharmaceutically acceptable salts thereof. More particularly it relates to new aminoglycoside derivatives and pharmaceutically acceptable salts thereof which have anti-viral activity, and immuno-stimulating activity and pharmaceutical compositions comprising the same. In addition, this invention also relates to methods of preparing the aminoglycoside derivatives and salts thereof.
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- Acylation of amino acids
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N-mono-substituted derivatives of diamino acids are prepared by the reaction of succinimidyl esters of carboxylic acids or substituted carbonic acids with the unprotected diamino acid. The acylation preferentially occurs at the side chain or terminal amino group of the diamino acid. For example, selective acylation of the terminal amino group of lysine occurs without first having protected the 2-amino group. Such acylation has application in the preparation of inter alia N6 -palmitoyl-lysine.
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