- Protection of ψ(CH2NH) peptide bond with 2,4-dimethoxybenzyl group in solid-phase peptide synthesis
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The reductive alkylation of a resin-bound amine by the Boc-amino aldehyde/NaBH3CN method is accompanied with undesirable double alkylation at Xaaψ(CH2NH)Gly sequences. To prevent the double alkylation, the utility of the 2,4-dimethox
- Sasaki, Yusuke,Abe, Junko
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Read Online
- Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers
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The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity
- Griffin, John H.,Linsell, Martin S.,Nodwell, Matthew B.,Chen, QiQi,Pace, John L.,Quast, Kelly L.,Krause, Kevin M.,Farrington, Lesley,Wu, Terry X.,Higgins, Deborah L.,Jenkins, Thomas E.,Christensen, Burton G.,Judice, J. Kevin
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Read Online
- Synthesis of triamino acid building blocks with different lipophilicities
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To obtain different amino acids with varying lipophilicity and that can carry up to three positive charges we have developed a number of new triamino acid building blocks. One set of building blocks was achieved by aminoethyl extension, via reductive amination, of the side chain of ortnithine, diaminopropanoic and diaminobutanoic acid. A second set of triamino acids with the aminoethyl extension having hydrocarbon side chains was synthesized from diaminobutanoic acid. The aldehydes needed for the extension by reductive amination were synthesized from the corresponding Fmoc-L-2-amino fatty acids in two steps. Reductive amination of these compounds with Boc-L-Dab-OH gave the C4-C8 alkyl-branched triamino acids. All triamino acids were subsequently Boc-protected at the formed secondary amine to make the monomers appropriate for the N-terminus position when performing Fmoc-based solid-phase peptide synthesis.
- Maity, Jyotirmoy,Honcharenko, Dmytro,Str?mberg, Roger
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Read Online
- A Fmoc-based submonomeric strategy for the solid phase synthesis of optically pure chiral PNAs
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A new submonomeric approach for the Fmoc solid phase synthesis of chiral PNAs is reported here. The design and synthesis of a new d-lysine-based Fmoc submonomer obtained by replacing the nucleobase residue with an Alloc group, compatible with Fmoc chemistry, is described starting from d-lysine and Fmoc-aminoacetaldehyde. The desired submonomer was obtained in high yield with no racemization. The conditions for synthesizing a chiral PNA dimer on solid support by a submonomeric approach have been optimized, allowing to obtain the desired PNA with a very high optical purity.
- Tedeschi, Tullia,Sforza, Stefano,Maffei, Francesca,Corradini, Roberto,Marchelli, Rosangela
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Read Online
- Solid-phase synthesis of PhTX-3.2.4 and PhTX-2.3.3 derivatives
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A new solid-phase method for the synthesis of derivatives of the philanthotoxins is described. Diamines are attached as carbamates to hydroxymethyl polystyrene resin. Selective mono-alkylations by acid-labile, substituted benzhydryl chlorides, followed by reductive alkylations with Fmoc-protected amino aldehydes are employed to assemble the polyamine backbone. Different acid-stability of the benzhydrylic protective groups allows the selective removal from secondary amines for subsequent branching.
- J?nsson, Daniel
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Read Online
- [1,2,4]TRIAZOLO[1,5-C]QUINAZOLIN-5-AMINES
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The present invention covers [1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds of general formula (I) in which R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.
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Page/Page column 241
(2021/02/19)
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- Development and preclinical evaluation of new inhaled lipoglycopeptides for the treatment of persistent pulmonary methicillin-resistant staphylococcus aureus infections
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Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
- Plaunt, Adam J.,Rose, Sasha J.,Kang, Jeong Yeon,Chen, Kuan-Ju,LaSala, Daniel,Heckler, Ryan P.,Dorfman, Arielle,Smith, Barrett T.,Chun, Donald,Viramontes, Veronica,Macaluso, Antonio,Li, Zhili,Zhou, Yuchen,Mark, Lilly,Basso, Jessica,Leifer, Franziska G.,Corboz, Michel R.,Chapman, Richard W.,Cipolla, David,Perkins, Walter R.,Malinin, Vladimir S.,Konicek, Donna M.
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supporting information
(2021/06/22)
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- PEPTIDE NUCLEIC ACID (PNA) MONOMERS WITH AN ORTHOGONALLY PROTECTED ESTER MOIETY
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This application pertains to orthogonally protected esters of peptide nucleic acid (PNA) monomers, which ester groups can be removed under conditions that permit typical backbone and side chain acid- and base-labile protecting groups to remain substantially intact thereby permitting the high yield of PNA monomer carboxylic acids that are suitable for use in PNA oligomer synthesis. Exemplary ester groups include, but are not limited to, 2,2,2-trichloroethyl (TCE), 2,2,2-tribromoethyl (TBE), 2-bromoethyl (2-BE) and 2-iodoethyl groups (2-IE). This invention also pertains to novel methods for the synthesis of Backbone Ester compounds and related Backbone Ester Acid Salts.
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Paragraph 00302; 00304; 00305
(2018/10/19)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 001283; 001284
(2018/09/12)
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- Inverse γ-Turn-Inspired Peptide: Synthesis and Analysis of Segetalin A Indole Hemiaminal
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Substitution of a peptide bond for an imine transforms the irreversible macrocyclization of peptides into a reversible process. The inherent cyclization tendency of a linear peptide is then analyzable through the equilibrium between the aldehyde and the imine by virtue of the higher reactivity of the corresponding linear peptide aldehyde. The tryptophan side chain of segetalin A aldehyde forms a 12-membered cyclic indole hemiaminal instead of the 18-membered macrocyclic imine expected. Herein, we analyzed this uncommon hemiaminal that shows that the biosynthesis of cyclic peptides is not necessarily based on linear precursor peptides with a high inherent macrolactamization tendency. By substituting a peptide bond for an imine, the cyclization tendency of a linear peptide can be analyzed through equilibration of the aldehyde and imine forms. The tryptophan side chain of segetalin A aldehyde forms a 12-membered cyclic indole hemiaminal instead of the expected 18-membered macrocyclic imine. Herein, we analyze this uncommon hemiaminal.
- Lamping, Matthias,Enck, Sebastian,Geyer, Armin
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p. 7443 - 7448
(2016/01/26)
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- NHC-Cu-catalyzed addition of propargylboron reagents to phosphinoylimines. Enantioselective synthesis of trimethylsilyl-substituted homoallenylamides and application to the synthesis of S-(-)-cyclooroidin
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A catalytic method for the efficient and enantioselective addition of a 1-trimethylsilyl-substituted allene moiety to phosphinoylimines is presented. Transformations are promoted by 5.0 mol % of a copper complex of an N-heterocyclic carbene in the presenc
- Mszar, Nicholas W.,Haeffner, Fredrik,Hoveyda, Amir H.
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supporting information
p. 3362 - 3365
(2014/03/21)
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- Tailoring of integrin ligands: Probing the charge capability of the metal ion-dependent adhesion site
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Intervention in integrin-mediated cell adhesion and integrin signaling pathways is an ongoing area of research in medicinal chemistry and drug development. One key element in integrin-ligand interaction is the coordination of the bivalent cation at the me
- Bollinger, Markus,Manzenrieder, Florian,Kolb, Roman,Bochen, Alexander,Neubauer, Stefanie,Marinelli, Luciana,Limongelli, Vittorio,Novellino, Ettore,Moessmer, Georg,Pell, Reinhard,Lindner, Wolfgang,Fanous, Joseph,Hoffman, Amnon,Kessler, Horst
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experimental part
p. 871 - 882
(2012/03/26)
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- Synthesis and nucleic acids binding properties of diastereomeric aminoethylprolyl peptide nucleic acids (aepPNA)
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A general synthetic method for Fmoc-protected monomers of all four diastereomeric aminoethyl peptide nucleic acid (aepPNA) has been developed. The key reaction is the coupling of nucleobase-modified proline derivatives and Fmoc-protected aminoacetaldehyde by reductive alkylation. Oligomerization of the aepPNAs up to 10mer was achieved by Fmoc-solid phase peptide synthesis methodology. Preliminary binding studies of these aepPNA oligomers with nucleic acids suggested that the "cis-" homothymine aepPNA decamers with (2′R,4′R) and (2′S,4′S) configurations can bind, albeit with slow kinetics, to their complementary RNA [poly(adenylic acid)] but not to the complementary DNA [poly(deoxyadenylic acid)]. On the other hand, the trans homothymine aepPNA decamers with (2′R,4′S) and (2′S,4′R) configurations failed to form stable hybrid with poly(adenylic acid) and poly(deoxyadenylic acid). No hybrid formation could be observed between a mixed-base (2′R,4′R)-aepPNA decamer with DNA and RNA in both antiparallel and parallel orientations. Copyright Taylor and Francis Group, LLC.
- Ngamwiriyawong, Patcharee,Vilaivan, Tirayut
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experimental part
p. 97 - 112
(2011/10/19)
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- CHEMICAL LINKERS AND CLEAVABLE SUBSTRATES AND CONJUGATES THEREOF
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The present disclosure provides drug-ligand conjugates and drug-cleavable substrate conjugates that are potent cytotoxins. The disclosure is also directed to compositions containing the drug-ligand conjugates, and to methods of treatment using them.
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(2010/06/19)
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- Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the SH2 domain of signal transducer and activator of transcription 3
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In cancer cells, signal transducer and activator of transcription 3 (Stat3) participates in aberrant growth, survival, angiogenesis, and invasion signals and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. One of the important elements of the recognition sequence, pTyr-Xxx-Xxx-Gln, is glutamine. We incorporated novel Gln mimics into a lead peptide, pCinn-Leu-Pro-Gln-NHBn, and found that a linear, unconstrained side chain and carboxamide are necessary for high affinity, and the benzamide can be eliminated. Replacement of Gln-NHBn with (R)-4-aminopentanamide or 2-aminoethylurea produced inhibitors with equal or greater potency than that of the lead, as judged by fluorescence polarization (IC50 values were 110 and 130 nM, respectively). When Pro was replaced with cis-3,4- methanoproline, the glutamine mimic, (4R,5S)-4-amino-5-benzyloxyhexanamide resulted in an IC50 of 69 nM, the highest affinity Stat3 inhibitor reported to date. 2009 American Chemical Society.
- Mandal, Pijus K.,Ren, Zhiyong,Chen, Xiaomin,Xiong, Chiyi,McMurray, John S.
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scheme or table
p. 6126 - 6141
(2010/03/24)
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- Small molecule compositions for sexual dysfunction
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Compounds of the general formula: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined. Further provided are methods for treatment of sexual dysfunction, including erectile dysfunction and female sexual dysfunction, and combination drugs and method of use thereof, including a compound of the invention and one or more second sexual dysfunction pharmaceutical agents.
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Page/Page column 28
(2009/07/03)
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- A practical and efficient approach to PNA monomers compatible with Fmoc-mediated solid-phase synthesis protocols
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A straightforward synthesis of orthogonally protected PNA monomers is described. Protected aminoethylglycine (Aeg) monomers were efficiently prepared by reductive amination of N-Fmoc-glycinaldehyde with glycine methyl ester and the subsequent acylation of
- Porcheddu, Andrea,Giacomelli, Giampaolo,Piredda, Ivana,Carta, Mariolino,Nieddu, Giammario
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experimental part
p. 5786 - 5797
(2009/06/08)
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- DMSO-aided o-iodoxybenzoic acid (IBX) oxidation of Fmoc-protected amino alcohols
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A fast and highly convenient procedure for the formation of Fmoc-protected amino aldehydes from the corresponding alcohols using 1.1 equiv. of IBX in the presence of dimethylsulfoxide (DMSO) is discussed. This procedure leads to the clean synthesis of Fmo
- Chen, Jack J.,Aduda, Vince
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p. 3493 - 3499
(2008/03/13)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- NOVEL SAFRAMYCIN ANALOGS AS THERAPEUTIC AGENTS
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The present invention is directed to saframcyin analogs that are useful in the treatment of cancer. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
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(2008/06/13)
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- NOVEL SAFRAMYCIN ANALOGS AS THERAPEUTIC AGENTS
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The present invention is directed to saframcyin analogs that are useful in the treatment of cancer. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.
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Page/Page column 57
(2010/02/15)
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- Solid-phase synthesis of peptide vinyl sulfones as potential inhibitors and activity-based probes of cysteine proteases
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(Matrix presented) Peptide vinyl sulfones were prepared from 2-chlorotrityl resin-bound phenolic amino vinyl sulfones in high yield and purity. This method enables the convenient synthesis of peptide vinyl sulfones having different amino acids at the Psu
- Wang, Gang,Mahesh, Uttamchandani,Chen, Grace Y. J.,Yao, Shao Q.
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p. 737 - 740
(2007/10/03)
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- Facile synthesis and cleavage of imidazolidines in a novel protection strategy for the preparation of peptides containing a reduced amide bioisostere
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Unsymmetrical imidazolidines were obtained in 75-91% yield by treating monoalkoxycarbonyl vicinal diamines at room temperature with aqueous 37% formaldehyde in the presence of Montmorillonite KSF as a solid catalyst. The imidazolidines were shown to be useful intermediates in a novel protection strategy for the synthesis of peptide analogues containing a reduced glycine amide bioisostere. The imidazolidine intermediate was cleaved conveniently and efficiently by 50% TFA in methylene chloride.
- Zhao, Jun,Pattaropong, Vatee,Jiang, Yongying,Hu, Longqin
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p. 229 - 232
(2007/10/03)
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- Glycopeptide derivatives
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Disclosed are derivatives of glycopeptide antibiotic compounds having at least one substituent of the formula: —Ra—Y—Rb—(Z)x where Ra, Rb, Y, Z and x are as defined, and having a group W at the glucose C-6 position, where W is as defined; and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.
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- A simple and advantageous protocol for the oxidation of alcohols with o-iodoxybenzoic acid (IBX)
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(figure presented) An efficient, user-friendly procedure for the oxidation of alcohols using IBX is described. Simply heating a solution of the alcohol in the presence of suspended IBX followed by filtration and removal of the solvent gives excellent yiel
- More, Jesse D.,Finney, Nathaniel S.
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p. 3001 - 3003
(2007/10/03)
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- Repetitive solid-phase synthesis of polyamines
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A repetitive solid-phase method for the synthesis of polyamines is described. Primary amino groups attached to a crosslinked polystyrene resin are monoalkylated by acid labile, benzhydryl-based alkyl chlorides. Reductive alkylation of the resulting secondary amino group by Fmoc-protected aminoaldehydes gives a N-benzhydryl polyamine backbone. Treatment of the resin with trifluoroacetic acid cleaves both the benzhydryl protective group and the polyamine derivative from the resin. By using benzhydryl protective groups with different acid stability, unbranched, branched and partly branched polyamines are synthesized.
- J?nsson, Daniel,Undén, Anders
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p. 3125 - 3128
(2007/10/03)
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- Glycopeptide derivatives and pharmaceutical compositions containing the same
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Disclosed are derivatives of glycopeptide compounds having at least one substituent of the formula: —Ra—Y—Rb—(Z)x where Ra, Rb, Y, Z and x are as defined, and pharmaceutical compositions containing such glycopeptide derivatives. The disclosed glycopeptide derivatives are useful as antibacterial agents.
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- Synthesis Using a Fmoc-Based Strategy and Biological Activities of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A
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Eight analogues of Dyn A(1-11)-NH2 incorporating the enzymatically stable Ψ(CH2-NH) isosteric peptide bond replacement were synthesized and tested for binding affinity at the central opioid μ, δ, and κ receptors in guinea pig brain (GPB) homogenates and f
- Meyer, Jean-Philippe,Davis, Peg,Lee, Katharine B.,Porreca, Frank,Yamamura, Henry I.,Hruby, Victor J.
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p. 3462 - 3468
(2007/10/03)
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- Formation of bis (Fmoc-amino ethyl)-N-glycine derivatives by reductive amination of Fmoc-amino aldehydes with NaBH3CN
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Unexpected results of the reductive amination of Fmoc-amino aldehydes by NaBH3CN are described. From glycine and Fmoc-4-t-Butoxy-tyrosinal, a small amount of double condensation product was obtained beside the initially desired product Fmoc-Tyr(OtBu)-ψ(CH2NH)-Gly-OH. From glycine methyl ester and Fmoc-glycinal, we only recovered the reduced peptide bond isostere, but from glycine and Fmoc-glycinal, bis(Fmoc-amino ethyl)-N-glycine was obtained as a major product.
- Salvi, Jean-Paul,Walchshofer, Nadia,Paris, Joelle
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p. 1181 - 1184
(2007/10/02)
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