- Simple methods for tracking stem cells with 64Cu-labeled DOTA-hexadecyl-benzoate
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The purpose of this study was to evaluate 64Cu-labeled hexadecyl-1,4,7,10-tetraazacyclododecane-tetraacetic acid-benzoate (64Cu-DOTA-HB) (1) as positron emission tomography (PET) radiotracer for stem cell imaging. Hexadecyl-DOTA-benzoate (DOTA-HB) (2) was efficiently labeled with 64Cu (>99%), and cell labeling efficiency with adipose-derived stem cells (ADSCs) was over 50%. Labeling with 1 did not compromise cell viability. In the PET imaging, intramuscularly transplanted 1-labeled ADSCs were monitored for 18 h in normal rat heart. These results indicate that 1 can be utilized as a promising radiotracer for monitoring of transplanted stem cells.
- Kim, Min Hwan,Woo, Sang-Keun,Kim, Kwang Il,Lee, Tae Sup,Kim, Chan Wha,Kang, Joo Hyun,Kim, Byung Il,Lim, Sang Moo,Lee, Kyo Chul,Lee, Yong Jin
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Read Online
- Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin
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Human α1-antitrypsin (hAAT) has two distinguishing functions: anti-protease activity and regulation of the immune system. In the present study we hypothesized that those two protein functions are mediated by different structural domains on the hAAT surface. Indeed, such biologically active immunoregulatory sites (not associated with canonical anti-protease activity) on the surface of hAAT were identified by in silico methods. Several peptides were derived from those immunoregulatory sites. Four peptides exhibited impressive biological effects in pharmacological concentration ranges. Peptidomimetic (14) was developed, based on the structure of the most druggable and active peptide. The compound exhibited a potent anti-inflammatory activity in vitro and in vivo. Such a compound could be used as a basis for developing novel anti-inflammatory drug candidates and as a research tool for better understanding hAAT functions.
- Lior, Yotam,Shtriker, Efrat,Kahremany, Shirin,Lewis, Eli C.,Gruzman, Arie
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supporting information
(2021/11/16)
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- Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
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The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
- Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
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supporting information
p. 4567 - 4587
(2021/05/06)
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- The spectrum between substrates and inhibitors: Pinpointing the binding mode of dengue protease ligands with modulated basicity and hydrophobicity
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Peptides can be inhibitors and substrates of proteases. The present study describes the inhibitor- vs. substrate-like properties of peptidic ligands of dengue protease which were designed to provide insight into their binding modes. Of particular interest was the localization of the cleavable peptide bond and the placement of hydrophobic elements in the binding site. The findings provide clues for the design of covalent inhibitors in which electrophilic functional groups bind to the catalytic serine, and in addition for the development of inhibitors that are less basic than the natural substrate and therefore have an improved pharmacokinetic profile. We observed a tendency of basic elements to favor a substrate-like binding mode, whereas hydrophobic elements decrease or eliminate enzymatic cleavage. This indicates a necessity to include basic elements which closely mimic the natural substrates into covalent inhibitors, posing a challenge from the chemical and pharmacokinetic perspective. However, hydrophobic elements may offer opportunities to develop non-covalent inhibitors with a favorable ADME profile and potentially improved target-binding kinetics.
- Gottscheber, Nicole,Hacker, Christina N.,Klein, Christian D.,Dra?i?, Tonko,Kühl, Nikos
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supporting information
(2021/10/02)
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- Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
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Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
- Osko, Jeremy D.,Porter, Nicholas J.,Narayana Reddy, Poli Adi,Xiao, You-Cai,Rokka, Johanna,Jung, Manfred,Hooker, Jacob M.,Salvino, Joseph M.,Christianson, David W.
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p. 295 - 308
(2020/02/20)
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- Dual PPAR-δ PPAR-γ agonists
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The present disclosure provides novel compounds with activity as PPARβ/δ and PPARγ dual agonists. The disclosure also provides methods of treating diabetes mellitus and methods of treating Alzheimer's disease utilizing the novel compounds, as well as phar
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Page/Page column 89
(2016/09/26)
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- ANTIMICROBIAL COMPOUNDS
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The invention provides compounds for use in treating microbial infection in an animal. Example compounds include Pyridin-3-ylmethyl (4-((2-aminophenyl)- carbamoyl)benzyl)carbamate ("Entinostat"). The compounds can act via induction of the innate antimicrobial peptide defense system, and stimulation of autophagy.
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Page/Page column 39
(2015/05/19)
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- Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6
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A series of protease activated receptor 2 activating peptide (PAR2-AP) derivatives (1-15) were designed and synthesized. The obtained compounds were tested on a panel of human kallikreins (hKLK1, hKLK2, hKLK5, hKLK6, and hKLK7) and were found completely i
- Severino, Beatrice,Fiorino, Ferdinando,Corvino, Angela,Caliendo, Giuseppe,Santagada, Vincenzo,Assis, Diego Magno,Oliveira, Juliana R.,Juliano, Luiz,Manganelli, Serena,Benfenati, Emilio,Frecentese, Francesco,Perissutti, Elisa,Juliano, Maria Aparecida
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- Design, development and evaluation of novel dual PPARδ/PPARγ agonists
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Type 2 diabetes is at epidemic proportions and thus development of novel pharmaceutical therapies for improving insulin sensitivity has become of paramount importance. The objectives of the current study were to develop novel dual PPARγ/δ agonists without
- Gathiaka, Symon,Nanayakkara, Gayani,Boncher, Tracey,Acevedo, Orlando,Wyble, Johnathon,Patel, Sagar,Patel, Akash,Shane, Mary Elizabeth,Bonkowski, Blake,Wieczorek, Jason,Rong, Yinghui,Huggins, Kevin,Smith, Forest,Amin, Rajesh H.
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p. 873 - 879
(2013/02/23)
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- Redox-based probes for protein tyrosine phosphatases
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Three in one: The design strategy for redox-based probes (RBPs) that detect the reversible oxidation of protein tyrosine phosphatases (PTPs) includes a "warhead" that forms a covalent adduct with the oxidized active site cysteine of PTPs, a synthetic module that directs binding to the PTP active site, and a chemical reporter tag used for the identification, purification, or direct visualization of the probe-labeled proteins (see picture). Copyright
- Leonard, Stephen E.,Garcia, Francisco J.,Goodsell, David S.,Carroll, Kate S.
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supporting information; experimental part
p. 4423 - 4427
(2011/06/26)
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- Direct Fmoc-chemistry-based solid-phase synthesis of peptidyl thioesters
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Attachment of a growing peptide chain to a glycylaminomethyl resin via a thioglycinamide bond is compatible with Fmoc-chemistry solid-phase peptide synthesis. Subsequent S-alkylation of the thioamide gives a thioimide that, on treatment with aqueous trifl
- Sharma, Indrajeet,Crich, David
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scheme or table
p. 6518 - 6524
(2011/10/02)
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- DNA-polyfluorophore excimers as sensitive reporters for esterases and lipases
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DNA-scaffolded oligodeoxyriboside fluorophores (ODFs) were used as the reporters in turn-on sensing of enzymatic bond-cleaving activity. A tetramer ODF of pyrene deoxynucleosides displayed high quenching efficiency when conjugated via ester linkages with
- Dai, Nan,Teo, Yin Nah,Kool, Eric T.
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supporting information; experimental part
p. 1221 - 1223
(2010/06/15)
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- Basic techniques of working on a solid phase: From ABC of the peptide synthesis to libraries of non-natural amino acids
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Libraries of hardly available amino acids bearing a heteroaromatic ring (2-pyrimidyl, substituted 2-pyridyl or 2-thiazolyl) at the amino group were prepared using solid-phase synthesis on various resins. The synthesized compounds are structurally similar to some known antidiabetic drugs. The paper combines features of a review (elementary introduction to the solid-phase synthesis methodology and technique for beginners and selected methods from peptide chemistry) and step-by-step experimental protocols (tested by the authors) useful as a methodic tool. The presented protocols (immobilization and modification of amino acids, placing and removal of common protective groups) require no sophisticated equipment and may be useful as pictorial introductory tasks for students education. Pleiades Publishing, Ltd., 2010.
- Babaev,Ermolat'ev
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experimental part
p. 2572 - 2589
(2011/04/15)
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- Solid-phase synthesis of azidomethylene inhibitors targeting cysteine proteases
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An efficient strategy for the solid-phase synthesis of azidomethylene inhibitors targeting cysteine proteases is described. The method is highlighted by its compatibility with readily available building blocks, as well as its ability to accommodate differ
- Yang, Peng-Yu,Wu, Hao,Lee, Mei Yin,Xu, Ashley,Srinivasan, Rajavel,Yao, Shao Q.
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supporting information; experimental part
p. 1881 - 1884
(2009/04/18)
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- FACILITATED FORWARD CHEMICAL GENETICS USING TAGGED TRIAZINE LIBRARY
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A novel tagged triazine library is provided in which three building blocks are prepared separately and assembled orthogonally to yield 1536 highly pure compounds. Each library compound contains a variety of a triethyleneglycol (TG) linker t one of the div
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Page 18-19; 27-28
(2010/02/09)
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- Dioxanes and uses thereof
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In recognition of the need to develop novel therapeutic agents and efficient methods for the synthesis thereof, the present invention provides novel compounds of general formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1, R2, R3, n, X and Y are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The present invention further provides compounds capable of inhibiting histone deacetylatase activity and methods for treating disorders regulated by histone deacetylase activity (e.g., cancer and protozoal infections) comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof. The present invention additionally provides methods for modulating the glucose-sensitive subset of genes downstream of Ure2p. The present invention also provides methods for preparing compounds of the invention.
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- Facilitated forward chemical genetics using a tagged triazine library and zebrafish embryo screening
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An improved forward chemical genetics approach was successfully demonstrated using a tagged library concept. A small-molecule triazine library with linkers was used to screen for brain/eye developmental phenotypes in a zebrafish embryo system. This approa
- Khersonsky, Sonya M.,Jung, Da-Woon,Kang, Tae-Wook,Walsh, Daniel P.,Moon, Ho-Sang,Jo, Hakryul,Jacobson, Eric M.,Shetty, Vivekananda,Neubert, Thomas A.,Chang, Young-Tae
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p. 11804 - 11805
(2007/10/03)
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- Dioxanes and uses thereof
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In recognition of the need to develop novel therapeutic agents and efficient methods for the synthesis thereof, the present invention provides novel compounds of general formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1, R2, R3, n, X and Y are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The present invention further provides compounds capable of inhibiting histone deacetylatase activity and methods for treating disorders regulated by histone deacetylase activity (e.g., cancer and protozoal infections) comprising administering a therapeutically effective amount of a compound of formula (1) to a subject in need thereof. The present invention additionally provides methods for modulating the glucose-sensitive subset of genes downstream of Ure2p.
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- Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin.
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Seventy-two hundred potential inhibitors of the histone deacetylase (HDAC) enzyme family, based on a 1,3-dioxane diversity structure, were synthesized on polystyrene macrobeads. The compounds were arrayed for biological assays in a "one bead-one stock sol
- Sternson,Wong,Grozinger,Schreiber
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p. 4239 - 4242
(2007/10/03)
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- Large-scale syntheses of FMOC-protected non-proteogenic amino acids: Useful building blocks for combinatorial libraries
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Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarbo
- Dener, Jeffrey M.,Fantauzzi, Pascal P.,Kshirsagar, Tushar A.,Kelly, Daphne E.,Wolfe, Aaron B.
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p. 445 - 449
(2013/09/07)
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- Para-aminomethylaryl carboxamide derivatives
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para-Aminomethylaryl carboxamides of Formula I are antagonists of VLA-4 and/or α4β7, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of asthma, allergies, inflammation, multiple sclerosis, and other inflammatory and autoimmune disorders.
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- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
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A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
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p. 161 - 175
(2007/10/03)
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- Solid phase synthesis of oligomeric guanidiniums
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Oligomers containing guanidinium linkages prepared via solid phase organic synthesis are of interest as possible therapeutic agents and in the assembly of supramolecular architectures. Efficient routes to these oligomers must be developed before their potential may be fully realized. Herein, four routes for their stepwise solid phase synthesis are described. In the first, a resin-bound thiourea was converted to a guanidinium using 2-chloro-1- methylpyridinium iodide. The second method utilized aza-Wittig couplings to prepare guanidiniums from resin-bound carbodiimides. Next, highly activated monomers prepared from bis-tert-butyloxycarbonythioureas and 2,4- dinitrofluorobenzene formed guanidiniums upon reaction with terminal amines. The optimum route, however, relied upon the 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride promoted coupling of a protected thiourea monomer with a resin-bound amine to produce the guanidinium linkage. The thiourea monomers for this method are easily prepared from mono-protected diamines and benzoyl- or Fmoc-isothiocyanate. The procedure is straightforward, proceeds cleanly in a relatively short period of time, and is compatible with several functional groups.
- Schneider, Stephen E.,Bishop, Patricia A.,Salazar, Mary Alice,Bishop, Owen A.,Anslyn, Eric V.
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p. 15063 - 15086
(2007/10/03)
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