- Asymmetric 1,4-Addition Reactions Catalyzed by N-Terminal Thiourea-Modified Helical l-Leu Peptide with Cyclic Amino Acids
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N-terminal thiourea-modified l-Leu-based peptide {(3,5-diCF3Ph)NHC(=S)-(l-Leu-l-Leu-Ac5c)2-OMe} with five-membered ring α,α-disubstituted α-amino acids (Ac5c) catalyzed a highly enantioselective 1,4-addition reaction between β-nitrostyrene and dimethyl malonate. The enantioselective reaction required only 0.5 mol % chiral peptide-catalyst in the presence of iPr2EtN (2.5 equiv.), and gave a 1,4-adduct with 93 % ee of an 85 % yield. As Michael acceptors, various β-nitrostyrene derivatives such as methyl, p-fluoro, p-bromo, and p-methoxy substituents on the phenyl group, 2-furyl, 2-thiophenyl, and naphthyl β-nitroethylenes could be applied. Furthermore, various alkyl malonates and cyclic β-keto-esters could be used as Michael donors. It became clear that the length of the peptide chain, a right-handed helical structure, amide N?Hs, and the N-terminal thiourea moiety play crucial roles in asymmetric induction.
- Sato, Kazuki,Umeno, Tomohiro,Ueda, Atsushi,Kato, Takuma,Doi, Mitsunobu,Tanaka, Masakazu
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supporting information
p. 11216 - 11220
(2021/06/21)
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- 2-AMINO-N-(AMINO-OXO-ARYL-LAMBDA6-SULFANYLIDENE)ACETAMIDE COMPOUNDS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 2-amino-N-(amino-oxo-aryl-λ6- sulfanylidene)acetamide compounds (referred to herein as ANASIA compounds) that, inter alia, inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase; to treat disorders that are ameliorated by the inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetase; to treat bacterial infections; etc.
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Page/Page column 97
(2021/06/26)
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- Synthesis of pyrimidine nucleoside and amino acid conjugates
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The synthesis of novel pyrimidine nucleoside bioconjugates with amino acids is presented. The N4-amino acid-acylated 2′-deoxycytidine analogues, modified with various amino acids, were synthesized using a three-step synthesis and obtained in moderate overall yields. Novel amino acid-alkylated 2′-deoxycytidine derivatives were obtained during the rearrangement of amino acid-acylated derivatives that occurred during Boc deprotection.
- Koplūnait?, Martyna,Butkut?, Kamil?,Me?kys, Rolandas,Taurait?, Daiva
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- Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome
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Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.
- Tereshchenkov, Andrey G.,Dobosz-Bartoszek, Malgorzata,Osterman, Ilya A.,Marks, James,Sergeeva, Vasilina A.,Kasatsky, Pavel,Komarova, Ekaterina S.,Stavrianidi, Andrey N.,Rodin, Igor A.,Konevega, Andrey L.,Sergiev, Petr V.,Sumbatyan, Natalia V.,Mankin, Alexander S.,Bogdanov, Alexey A.,Polikanov, Yury S.
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p. 842 - 852
(2018/02/26)
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- New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons
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An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.
- Wang, Lucia,Guillen, Valeria S.,Sharma, Naina,Flessa, Kevin,Min, Jian,Carlson, Kathryn E.,Toy, Weiyi,Braqi, Sara,Katzenellenbogen, Benita S.,Katzenellenbogen, John A.,Chandarlapaty, Sarat,Sharma, Abhishek
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supporting information
p. 803 - 808
(2018/07/21)
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- N,O-Bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis
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A method using N,O-bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis is descried. The coupling reaction between N-hydroxysuccinimide (NHS) esters and amines could be performed under mild conditions with N,O-bis(trimethylsilyl)acetamide (BSA) as coupling reagent and no additional acid/base is required. All byproducts and excessive reactants are water soluble or hydrolysable and easy to eliminate through water-washing at the purification stage. Moreover, all the reactants are inexpensive and widely used in conventional drug production.
- Huang, Ye,Feng, Wen-Hua
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p. 357 - 360
(2016/03/16)
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- Bispidine as a secondary structure nucleator in peptides
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Here we describe bispidine as a scaffold for inducing open turn-like and beta sheet conformations on the attached peptides depending on the mode of attachment of peptides to the scaffold. Various bispidine-peptide conjugates were designed and synthesized to demonstrate the versatility of the scaffold.
- Haridas,Sadanandan, Sandhya,Sharma, Yogesh K.,Chinthalapalli, Srinivas,Shandilya, Ashutosh
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supporting information; experimental part
p. 623 - 626
(2012/03/07)
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- A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
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A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.
- Jadhav, Sandip V.,Bandyopadhyay, Anupam,Benke, Sushil N.,Mali, Sachitanand M.,Gopi, Hosahudya N.
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supporting information; experimental part
p. 4182 - 4187
(2011/06/28)
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- Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors
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A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (β5) activity (IC50 = 0.28 and 0.51 μM, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at >1 μM concentrations of compound.
- Nakamura, Hiroyuki,Watanabe, Mizuyoshi,Ban, Hyun Seung,Nabeyama, Wataru,Asai, Akira
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scheme or table
p. 3220 - 3224
(2010/04/05)
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- Procedure for the oxidation of β-amino alcohols to α-amino aldehydes
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A novel procedure for the mild oxidation of β-amino alcohols to α-amino aldehydes using commercially available manganese(IV) oxide is reported. There are several important advantages of the new method, such as high enantiopurity of the reaction and the absence of either over-oxidation or any reaction by-products during the process. A number of N-protected L-α-amino aldehydes was obtained. All new compounds were characterized by their NMR spectra and optical rotation data. Georg Thieme Verlag Stuttgart.
- Sergeev, Maxim E.,Pronin, Victor B.,Voyushina, Tatiana L.
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p. 2802 - 2804
(2007/10/03)
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- CYCLIC HEMIACETAL DERIVATIVE AND USE THEREOF
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A compound represented by the following formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen, a halogen, a cyano group, a lower alkyl group or a lower alkoxy group, and n is 0 or 1, which has a calpain inhibitory activity, is provided.
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- Exploration of cornea permeable calpain inhibitors as anticataract agents
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To explore cornea permeable calpain inhibitors, four compounds displaying different characteristics were designed and synthesized based on the known potent calpain inhibitor, peptidyl aldehyde SJA6017. Two approaches were adopted; an improvement in the physicochemical properties, and conversion of the active aldehyde. The water-soluble peptidyl aldehyde 1 containing a pyridine ring at the P3 site showed a modest inhibition against calpains and an improvement of corneal permeability in comparison with SJA6017. Replacement of the aldehyde of SJA6017 by an α-ketoamide provided compound 2 that was approximately equipotent with SJA6017, but it was extremely water-insoluble. However, compound 3, in which the aldehyde was converted into a cyclic hemiacetal, proved to be a less potent calpain inhibitor than SJA6017, but demonstrated excellent transcorneal permeability. Further modification generating the cyclic hemiacetal 4 containing a thiourea linker between the P3 and P2 sites exhibited potent inhibitory activities, high cornea permeability and excellent efficacy in the rat lens culture cataract model.
- Nakamura, Masayuki,Yamaguchi, Masazumi,Sakai, Osamu,Inoue, Jun
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p. 1371 - 1379
(2007/10/03)
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- Antibody recognition of chiral surfaces. Enantiomorphous crystals of leucine-leucine-tyrosine
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Monoclonal antibodies were selected after immunization with crystals of the tripeptide L-leucine-L-leucine-L-tyrosine. They interact with the tripeptide crystals, but do not interact with the tripeptide molecule, with other crystalline surfaces, or with adsorbed protein. The interactions of two antibodies with crystals of L-Leu-L-Leu-L-Tyr and of its enantiomer D-Leu-D-Leu-D-Tyr were characterized in depth. Antibody 48E is stereoselective and enantioselective: it recognizes only the {011} faces of the L-Leu-L-Leu-L-Tyr crystals, and not the enantiomorphous {011} faces of D-Leu-D-Leu-D-Tyr crystals, or any other faces of either crystal. In contrast, antibody 602E is poorly stereoselective and is not enantioselective: it recognizes the crystals of both enantiomers, interacting with a number of different faces of each. The different recognition patterns are explained on the basis of the nature of the interactions and the structure of the interacting surfaces. Understanding this antibody specificity advances our general understanding of surface recognition and transfer of chiral information across biological interfaces.
- Geva, Merav,Frolow, Felix,Eisenstein, Miriam,Addadi, Lia
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p. 696 - 704
(2007/10/03)
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- O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis
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The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.
- Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
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p. 1661 - 1664
(2007/10/03)
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- Stabilized analogs of thymopentin. 1. 4,5-Ketomethylene pseudopeptides
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The pentapeptide, thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5) is known for its activity as an immunomodulating drug, but with limited half-life in plasma. In this first paper of a series of three studies, the synthesis of analogs stabilized at the peptide bond between the C-terminal amino acids via insertion of a ketomethylene moiety is described. N-Blocked pseudopeptides containing Val(k)Phe, Ala(k)Phe, and Val(k)Val units were prepared and attached to chloromethyl Merrifield resin via the carboxy terminal. Removal of the N-BOC group by trifluoroacetic acid was followed by sequential coupling with N-BOC dipeptides of aspartic acid to yield resin-bound N-BOC pseudotetrapeptides. Removal of N-BOC and coupling with N-BOC-r-N- tosylarginine followed by total cleavage of blocking groups and resin by HF afforded the target pseudopentapeptides. The analogs were found to compete favorably with thymopentin for binding to CEM cells, but binding was reduced by about 20-30% on average. All analogs showed significant enhancement of half-life versus thymopentin in mouse serum, but most showed only modest improvement in human serum. Insertion of proline or norleucine at position 2 in the chain caused a substantial increase in half-life (3-4-fold), while N- methylnorleucine conferred complete stability in the analogs.
- DeGraw, Joseph I.,Almquist, Ronald G.,Hiebert, Charles K.,Colwell, William T.,Crase, Jac,Hayano, Takeshi,Judd, Amrit K.,Dousman, Linda,Smith, R. Lane,Waud, William R.,Uchida, Itsuo
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p. 2386 - 2397
(2007/10/03)
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- Peptide inhibitors of IκB protease: Modification of the C-termini of Z-LLF-CHO
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A series of tripeptides (Z-LLF-R) with various modifications at their C-terminus were synthesized and evaluated for their ability to prevent the activation of NF-κB through inhibition of IκB protease. Of the compounds evaluated only the C-terminal aldehydes 5a,b were active in our Jurkat T-cell based assay. Compounds 5a also decreased IL-2 and IL-8 levels in these cells indicating that inhibitors of IκB protease can have an effect on various signalling pathways.
- Suto, Mark J.,Sullivan, Robert W.,Ransone, Lynn J.
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p. 2925 - 2930
(2007/10/03)
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- Tripodal peptides with chiral conformations stabilized by interstrand hydrogen bonds
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C3 symmetric trispeptides are described that form chiral conformations and are therefore eminently suited to provide a new family of chiral receptor molecules when extended by appropriate binding sites. These trispeptides are composed of C3 symmetric trisamines as anchors and three symmetrically extending chiral amino acid residues. Their conformations in apolar solvents fall into two main classes. One is comprised of propeller-like conformations of preferred chiral sense that are stabilized by a belt of intramolecular H-bonds (hydrogen bonds) between adjacent strands. The other class has two of its strands connected by two H-bonds to form a 10-membered ring, while the third strand may hydrogen-bond to one of the other two. The effect of the anchors and amino acids on the relative stability of the H-bonded, chiral conformations has been established by a combination of spectroscopic and theoretical means. Trispeptides derived from more lipophilic α-amino acids show a higher population of the chiral conformations. Moreover, trispeptides that are based on tris(2-aminoethyl)amine (TREN) as anchor form stronger H-bonds than those relying on 1,3,5-tris(aminomethyl)benzene (TRAM).
- Tor, Yitzhak,Libman, Jacqueline,Shanzer, Abraham,Felder, Clifford E.,Lifson, Shneior
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p. 6653 - 6661
(2007/10/02)
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- Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679
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A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.
- DeSolms,Giuliani,Guare,Vacca,Sanders,Graham,Wiggins,Darke,Sigal,Zugay,Emini,Schleif,Quintero,Anderson,Huff
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p. 2852 - 2857
(2007/10/02)
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- LE CHLOROFORMIATE D'ISOPROPENYLE (IPCF) EN CHIMIE DES AMINO-ACIDES ET DES PEPTIDES - III SYNTHESE D'ESTERS ACTIFS D'AMINO ACIDES N-PROTEGES
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Isopropenyl chloroformate (IPCF) was used for preparation of mixed carbonates (Aryl and isopropenyl) which are very suitable reagents for active ester synthesis of amino acid derivatives (Boc derivatives in particular).
- Jaouadi, M.,Selve, C.,Dormoy, J. R.,Castro, B.,Martinez, J.
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p. 1721 - 1722
(2007/10/02)
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