- Design, Synthesis, and Biological Activity of Isosyringolin A
-
Isosyringolin A, which is an isomer of the proteasome-inhibiting natural product syringolin A, was designed and synthesized to develop analogues that are step economical and synthetically accessible in a practical manner. It was revealed that isosyringolin A exhibited proteasome-inhibitory activity comparable to that of syringolin A and that its derivatization leads to great enhancement in its proteasome inhibitory activity as well as its cytotoxicity against human myeloma cells.
- Kitahata, Shun,Chiba, Takuya,Yoshida, Takashi,Ri, Masaki,Iida, Shinsuke,Matsuda, Akira,Ichikawa, Satoshi
-
-
Read Online
- Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites
-
There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet–Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds’ bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.
- Cockram, Peter E.,Turner, Callum A.,Slawin, Alexandra M. Z.,Smith, Terry K.
-
-
- Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine
-
Herein, we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a N-O bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of the configuration depending on the steric hindrance in the vicinity of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one.
- Bihel, Frédéric,Bricard, Jacques,Garnier, Delphine,Gizzi, Patrick,Leloire, Maeva,Mohr, Julie,Schmitt, Martine,Schneider, Séverine,Tang, Shuang-Qi
-
p. 15347 - 15359
(2020/11/30)
-
- PYRROLIDINE DERIVATIVE
-
The present invention aims to provide a novel compound which has CGRP receptor antagonist activity and which is useful for the treatment of various diseases mediated by CGRP receptors. That is, the present invention relates to the pyrrolidine derivatives represented by the following formula (I) or a pharmaceutically acceptable salt thereof. In the formulae, W is ring, X is a carbon atom or the like, Y1 to Y4 are carbon atoms or the like, and R1 to R7 is alkyl or the like. The compounds of the present invention or a pharmaceutically acceptable salt thereof have an excellent CGRP receptor antagonist activity, and thus are useful as agents for the treatment of various diseases mediated by CGRP receptors.
- -
-
Paragraph 0282
(2019/04/16)
-
- Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics
-
The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.
- Oueis, Emilia,Jaspars, Marcel,Westwood, Nicholas J.,Naismith, James H.
-
supporting information
p. 5842 - 5845
(2016/05/09)
-
- Radiolabeled antagonistic bombesin peptidomimetics for tumor targeting
-
The replacement of amide bonds in the backbone of peptides by proteolytically stable 1,2,3-triazole isosteres can provide novel peptidomimetics with promising properties for the development of tumor-targeting radiopeptides. On the basis of our previous work with radiolabeled agonistic bombesin (BBN) derivatives of the sequence [Nle14]BBN(7-14), we substituted selected amide bonds of the structurally closely related antagonistic peptide analog JMV594. With the exception of the C-terminal modification, amide-to-triazole substitutions tolerated by [Nle 14]BBN(7-14) without loss of biological function led to abolished receptor affinity in the case of JMV594. These findings provide an additional piece of evidence for the currently disputed differences in the modes of action of agonistic and antagonistic gastrin-releasing peptide receptor (GRPR)-targeting radiopeptides.
- Valverde, Ibai E.,Huxol, Elena,Mindt, Thomas L.
-
p. 275 - 278
(2014/05/06)
-
- Tosylhydrazide-promoted diastereoselective intramolecular 1,3-dipolar cycloadditions: Synthesis of tetrahydropyrrolo[3,4-c]pyrazoles
-
A very straightforward diastereoselective synthesis of tetrahydropyrrolo[3, 4-c]pyrazoles by intramolecular 1,3-dipolar cycloaddition is described. The starting materials for the synthetic route are N-Boc-protected α-amino acids, which are first transformed into N-allyl-α-amino ketones through conventional methodologies. Then, a one-pot sequence that involves formation of a tosylhydrazone from the ketone, base-induced decomposition of the hydrazone, and intramolecular 1,3-dipolar cycloaddition of the diazo compound generated, gives rise to the bicyclic systems with total diastereoselectivity and high preservation of the enantiomeric purity. However, the analogous process employing α-amino aldehydes lacks stereoselectivity. DFT computational modeling has been carried out to account for the different behavior of the two types of systems. Copyright
- Barroso, Raquel,Escribano, Maria,Cabal, Maria-Paz,Valdes, Carlos
-
p. 1672 - 1683
(2014/03/21)
-
- Tosylhydrazide-Promoted Diastereoselective Intramolecular 1,3-Dipolar Cycloadditions: Synthesis of Tetrahydropyrrolo[3,4-c]pyrazoles
-
A very straightforward diastereoselective synthesis of tetrahydropyrrolo[3,4-c]pyrazoles by intramolecular 1,3-dipolar cycloaddition is described. The starting materials for the synthetic route are N-Boc-protected α-amino acids, which are first transformed into N-allyl-α-amino ketones through conventional methodologies. Then, a one-pot sequence that involves formation of a tosylhydrazone from the ketone, base-induced decomposition of the hydrazone, and intramolecular 1,3-dipolar cycloaddition of the diazo compound generated, gives rise to the bicyclic systems with total diastereoselectivity and high preservation of the enantiomeric purity. However, the analogous process employing α-amino aldehydes lacks stereoselectivity. DFT computational modeling has been carried out to account for the different behavior of the two types of systems.
- Barroso, Raquel,Escribano, Maria,Cabal, Maria-Paz,Valdés, Carlos
-
p. 1672 - 1683
(2015/10/05)
-
- Synthesis of new simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety
-
In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,β- unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G2 and MCF7). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G2 cancer cell lines comparable to paclitaxel and ellipticine.
- The, Chinh Pham,Thi, Tuyet Anh Dang,Hoang, Thi Phuong,Ngo, Quoc Anh,Doan, Duy Tien,Thi, Thu Ha Nguyen,Thi, Tham Pham,Thi, Thu Ha Vu,Jean,Van De Weghe,Van, Tuyen Nguyen
-
supporting information
p. 2244 - 2246
(2014/05/20)
-
- 1,2,3-Triazoles as amide bond mimics: Triazole scan yields protease-resistant peptidomimetics for tumor targeting
-
The triazole makes the difference: Replacement of amide bonds in the backbone of peptides by 1,4-disubstituted 1,2,3-triazole isosteres affords peptidomimetics with retained receptor affinity and cell-internalization properties, enhanced proteolytic stability, and improved tumor-targeting capabilities. Copyright
- Valverde, Ibai E.,Bauman, Andreas,Kluba, Christiane A.,Vomstein, Sandra,Walter, Martin A.,Mindt, Thomas L.
-
supporting information
p. 8957 - 8960
(2013/09/02)
-
- Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology
-
The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction-Amine Deprotection-Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.
- Shaw, Arthur Y.,Medda, Federico,Hulme, Christopher
-
experimental part
p. 1313 - 1315
(2012/03/27)
-
- An expedient conversion of α-amino acids into Weinreb amides using COMU As a coupling agent
-
The use of COMU, as a non-hazardous partner, in the coupling of N-protected α-amino acids to N-methoxy-N-methylamine to afford the corresponding Weinreb amides is discussed. From a practical point of view the reaction can be monitored visually by virtue of the colour change associated with the conversion of substrates (yellow) into the products (orange). As the by-products of the reaction are conveniently water-soluble the products are isolated relatively pure and with minimal racemisation. These factors coupled with the short reaction time make this a very useful procedure.
- Tyrrell, Elizabeth,Brawn, Peter,Carew, Mark,Greenwood, Iain
-
experimental part
p. 369 - 372
(2011/02/28)
-
- Conversion of α-amino acids into bioactive o-aminoalkyl resorcylates and related dihydroxyisoindolinones
-
The synthesis of biologically active o-aminoalkyl resorcylates and related dihydroxyisoindolinones from functionalized α-amino acids without the use of phenolic protection is described. The key aminoalkyl-diketo-dioxinone intermediates were prepared utilizing a crossed Claisen condensation reaction in the presence of diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization, and subsequent modification provided the novel resorcylates which showed activity against a selection of receptors and kinases, including 5-HT and CDK.
- Patel, Bhavesh H.,Mason, Andrew M.,Patel, Hetal,Coombes, R. Charles,Ali, Simak,Barrett, Anthony G. M.
-
experimental part
p. 6209 - 6217
(2011/10/02)
-
- Pyrrole-based scaffolds for turn mimics
-
Two amino acid derived synthons were combined to give homopropargylic amines 2. Platinum dichloride was used to cyclize these intermediates into pyrroles 3 which collapsed to the target secondary structure mimics 1 on treatment with base. Side chains of these compounds overlay with an idealized type 1 β-turn and with an inverse γ-turn.(Figure Presented)
- Ko, Eunhwa,Burgess, Kevin
-
supporting information; experimental part
p. 980 - 983
(2011/04/22)
-
- Synthesis of α, β-unsaturated γ-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides
-
Mild, efficient and racemization-free synthesis of N-protected α, β-unsaturated γ-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous γ-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a β-sheet conformation, while mixed α- and α,β-unsaturated γ-hybrid dipeptide adapted an irregular structure in single crystals.
- Mali, Sachitanand M.,Bandyopadhyay, Anupam,Jadhav, Sandip V.,Kumar, Mothukuri Ganesh,Gopi, Hosahudya N.
-
supporting information; experimental part
p. 6566 - 6574
(2011/11/05)
-
- Total synthesis of syringolin A
-
(Equation Presented). A convergent, efficient synthesis of syringolin A has been accomplished in 13 steps from commercially available materials, Garners aldehyde and l-valine. The unnatural 3,4-dehydrolysine fragment was prepared using successive Johnson-Claisen/Curtius rearrangement reactions. The macrolactamization and late-stage introduction of the side chain will provide convenient access to analogues of this promising proteasome inhibitor.
- Dai, Chunhui,Stephenson, Corey R. J.
-
supporting information; experimental part
p. 3453 - 3455
(2010/10/02)
-
- Tin(ii) chloride assisted synthesis of N-protected γ-amino β-keto esters through semipinacol rearrangement
-
A facile synthetic route for the preparation of N-protected γ-amino β-keto esters from amino aldehydes and ethyl diazoacetate is described. The two component coupling is facilitated by tin(ii) chloride followed by semipinacol rearrangement leading to the product in quantitative yield. The reaction is mild, instantaneous and compatible with Boc-, Fmoc- and Cbz-amino protecting groups.
- Bandyopadhyay, Anupam,Agrawal, Neha,Mali, Sachitanand M.,Jadhav, Sandip V.,Gopi, Hosahudya N.
-
supporting information; experimental part
p. 4855 - 4860
(2010/12/24)
-
- Tri-peptide Inhibitors of Serine Elastases
-
The present invention provides compounds of formula (I): where X is R1—(CR3R4)nOC(O)—; R1—(CR3R4)nC(O)—; R1—C(O)NH(CR3R4)nOC(O)—; R1—C(O)NH(CR3R4)nC(O)—; R1—C(O)(CR3R4)nOC(O)—; or R1—C(O)(CR3R4)nC(O)—; where R1 is optionally substituted C5-10 aryl or heteroaryl; OH or NH2; where R3 and R4 are independently H or methyl; and n is 0 to 6; and Y is —CF3 or one of: where R2 is C1-8 alkyl optionally substituted with halo or —OH; —(CR6R7)p—C5-6 aryl optionally substituted with halo, —OH, C1-8 alkyl, C1-8 haloalkyl, —(CH2)mC(O)NH2 or —(CH2)mOCH3; where R6 and R7 are independently H or methyl; m is 0 to 4, and p is 0 or 1 or a pharmaceutically acceptable salt, ester, metabolite or prodrug thereof
- -
-
-
- Toward the back-up of Boceprevir (SCH 503034): Discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles
-
Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P4 pocket and optimization of the P1′ capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P4-capped inhibitors were also found to have improved PK profile.
- Bogen, Stéphane L.,Pan, Weidong,Ruan, Sumei,Nair, Latha G.,Arasappan, Ashok,Bennett, Frank,Chen, Kevin X.,Jao, Edwin,Venkatraman, Srikanth,Vibulbhan, Bancha,Liu, Rong,Cheng, Kuo-Chi,Guo, Zhuyan,Tong, Xiao,Saksena, Anil K.,Girijavallabhan, Viyyoor,Njoroge, F. George
-
scheme or table
p. 3679 - 3688
(2010/04/05)
-
- Synthesis of substituted pyrrolin-4-ones from amino acids in mild conditions via a gold-catalyzed approach
-
(Chemical Equation Presented) The gold-catalyzed cyclization of various α-amino-ynone derivatives gave the corresponding pyrrolin-4-ones in high yields. Moreover, the use of gold(III) oxide as catalyst allows a moderate to total stereocontrol during the cyclization. These pyrrolin-4-ones are highly useful intermediates for the synthesis of functionalized pyrrolidines and other natural products.
- Gouault, Nicolas,Le Roch, Myriam,Cornee, Carole,David, Michele,Uriac, Philippe
-
supporting information; experimental part
p. 5614 - 5617
(2009/12/08)
-
- NOVEL CATHEPSIN C INHIBITORS AND THEIR USE
-
The invention is directed to compounds according to Formula (I) wherein R1, R2a, R2b, R2c, R3, and n are defined below, and to pharmaceutically-acceptable salts thereof. They are cathepsin C inhibitors and can be used in the treatment of diseases mediated
- -
-
Page/Page column 92
(2009/04/25)
-
- DEFORMYLASE INHIBITOR, PROCESS FOR THE PREPARATION THEREOF, AND COMPOSITION COMPRISING THE SAME
-
Provided are a novel compound useful for a deformylase inhibitor with excellent antibacterial activity or its pharmaceutically acceptable salt, a process for preparing the same, and an antibacterial composition including the same as an active ingredient. The deformylase inhibitor has a broad spectrum against bacteria, including bacteria with resistance to existing antibacterial agents.
- -
-
Page/Page column 10-11
(2010/11/30)
-
- Design and synthesis of a novel class of furan-based molecules as potential 20S proteasome inhibitors
-
A novel class of furan-based compounds as potential 20S proteasome inhibitors have been designed and synthesized, among which nine compounds are peptide derivatives and six molecules are statine peptidomimetics. The C-terminal furanyl moiety was introduced to target molecules as furan-based amino acids. All the compounds were obtained steadily with moderate to high yield. Compound 12 was a selective moderate potent proteasome peptidomimetic inhibitor. It inhibited HepG2 and HL-60 proliferation effectively.
- Fu, Yiqiu,Xu, Bo,Zou, Xiaomin,Ma, Chao,Yang, Xiaoming,Mou, Ke,Fu, Gang,Lue, Yang,Xu, Ping
-
p. 1102 - 1106
(2007/10/03)
-
- β-isocupreidine-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes
-
β-Isocupreidine (β-ICD)-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) takes place without racemization and exhibits the match-mismatch relationship between the substrate and the catalyst. In the case of acyclic amino aldehydes, α,-substrates show excellent syn selectivity and high reactivity in contrast to L-substrates. On the other hand, in the case of cyclic amino aldehydes, D-substrates rather than L-substrates show excellent anti selectivity and high reactivity.
- Nakano, Ayako,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi
-
p. 5357 - 5360
(2007/10/03)
-
- Practical synthesis of fluorous oxazolidinone chiral auxiliaries from α-amino acids
-
A series of new fluorous-supported oxazolidinone chiral auxiliaries has been prepared using a versatile and general five-step pathway, starting from readily available chiral α-amino acids. The key feature of this synthesis is the efficient generation of a suitably active perfluoroalkyllithium species. By use of this protocol, the auxiliaries can be obtained in high enantiomeric purity and on multigram scales from L-phenylalanine and L-valine with overall yields as high as 55%. The new methodology also incorporates fluorous solid-phase extraction on the large scale, allowing bulk quantities (up to 25 g) of fluorous compounds to be purified from the crude reaction mixture.
- Hein, Jason E.,Geary, Laina M.,Jaworski, Ashley A.,Hultin, Philip G.
-
p. 9940 - 9946
(2007/10/03)
-
- Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors
-
Design, synthesis, and biological evaluation of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease (SARS-3CLpro) inhibitors for severe acute respiratory syndrome coronavirus (SARS-CoV) are described. These inhibitors exhibited antiviral activity against SARS-CoV in infected cells in the micromolar range. An X-ray crystal structure of our lead inhibitor (4) bound to SARS-3CLpro provided important drug-design templates for the design of small-molecule inhibitors.
- Ghosh, Arun K.,Xi, Kai,Ratia, Kiira,Santarsiero, Bernard D.,Fu, Wentao,Harcourt, Brian H.,Rota, Paul A.,Baker, Susan C.,Johnson, Michael E.,Mesecar, Andrew D.
-
p. 6767 - 6771
(2007/10/03)
-
- Antimicrobial agents
-
Compounds of formula (I) are antibacterial agents: wherein Z represents a radical of formula —N(OH)CH(=O) or of formula —C(=O)NH(OH), and R1-R4 are as defined in the specification. A method for the treatment of bacterial or protozoal infections in humans and non-human mammals, which comprises administering to a subject suffering such infection an antibacterially or antiprotozoally effective dose of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof.
- -
-
Page column 18
(2010/11/30)
-
- [Bis(2-methoxyethyl)amino]sulfur Trifluoride, the Deoxo-Fluor Reagent: Application toward One-Flask Transformations of Carboxylic Acids to Amides
-
The use of the Deoxo-Fluor reagent is a versatile method for acyl fluoride generation and subsequent one-flask amide coupling. It provides mild conditions and facile purification of the desired products in good to excellent yields. We have explored the utility of this reagent for the one-flask conversion of acids to amides and Weinreb amides and as a peptide-coupling reagent.
- White, Jonathan M.,Tunoori, Ashok Rao,Turunen, Brandon J.,Georg, Gunda I.
-
p. 2573 - 2576
(2007/10/03)
-
- Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues
-
The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized and evaluated in cell-based assays for both cytotoxic and antimitotic activity in order to explore the SAR for this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin (1), and consequently it has been subjected to thorough preclinical evaluation and targeted for clinical evaluation. The details of the synthesis of hemiasterlin (1) and the analogues and a discussion of how their biological activities vary with their structures are presented in this paper.
- Nieman, James A.,Coleman, John E.,Wallace, Debra J.,Piers, Edward,Lim, Lynette Y.,Roberge, Michel,Andersen, Raymond J.
-
p. 183 - 199
(2007/10/03)
-
- Total syntheses of lyngbyabellins A and B, potent cytotoxic lipopeptides from the marine cyanobacterium Lyngbya majuscula
-
The first total syntheses of lyngbyabellins A and B, Lyngbya majuscula derived lipopeptides, are described. The functionalized thiazole carboxylic acid units were prepared by the oxidative dehydrogenation of the corresponding thiazolidines with chemical manganese dioxide. The asymmetric synthesis of the dichlorinated β-hydroxy acid by a chiral oxazaborolidinone mediated aldol reaction. Finally, fragment condensation followed by macrolactamization provided lyngbyabellin A. The total synthesis of lyngbyabellin B was accomplished by formation of the sensitive thiazoline ring after the macrolactamization.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,Katagiri, Daichi,Aoyama, Toyohiko,Shioiri, Takayuki
-
p. 9445 - 9458
(2007/10/03)
-
- Synthesis and anti-Helicobacter pylori activity of pyloricidin derivatives. I. Structure-activity relationships on the terminal peptidic moiety
-
The novel natural antibiotics pyloricidin A, B and C possess potent and highly selective antibacterial activity against Helicobacter pylori. In order to investigate the structure activity relationships for the terminal peptidic moiety, a series of pyloricidin B and pyloricidin C derivatives, bearing various amino acids in the moiety, were prepared and evaluated for their anti-H. pylori activity. The derivatives bearing α-D-, β- and γ-amino acids or peptidemimetics showed drastically decreased activity. On the other hand, the derivatives with α-L-amino acids were found to maintain the activity. Among the derivatives prepared in this work, the allyglycine derivative 2s showed the most potent anti-H. pylori activity, with an MIC value of less than 0.006 μg/ml against H. pylori NCTC11637, which is 60-fold greater than the activity of the lead compound pyloricidin C.
- Hasuoka, Atsushi,Nishikimi, Yuji,Nakayama, Yutaka,Kamiyama, Keiji,Nakao, Masafumi,Miyagawa, Ken-Ichiro,Nishimura, Osamu,Fujino, Masahiko
-
p. 322 - 336
(2007/10/03)
-
- Synthesis of densely functionalized pyrrolidinone templates by an intramolecular oxo-Diels-Alder reaction
-
Preparation of densely functionalized pyrrolidinone templates, is a challenge for synthetic chemists. These templates are important building blocks for novel conformationally constrained natural products or for library generation of highly functionalized
- Murray, William V.,Mishra, Pranab K.,Sun, Sengen,Maden, Amy
-
p. 7389 - 7392
(2007/10/03)
-
- Synthesis of new chiral peptide nucleic acid (PNA) monomers
-
We have synthesised a series of new chiral type I peptide nucleic acid monomers in total yields of 36-53%, derived from Val, Ile, Ser(Bzl), Pro, and Trp, employing convenient procedure.
- Falkiewicz,Wisniowski,Kolodziejczyk,Wisniewski
-
p. 1393 - 1397
(2007/10/03)
-
- Improved synthesis of a new nonpeptidic inhibitor of human neutrophil elastase
-
A practical method for the synthesis of ONO-6818 {2-(5-Amino-6-oxo-2-phenylhydropyrimidinyl)-N-[2-(5-tert-butyl-1,3,4-oxadiazo l-2-yl)-1-(methylethyl)-2-oxoethyl]acetamide} (1), the first clinical candidate for a nonpeptidic orally active inhibitor of hum
- Ohmoto,Yamamoto,Horiuchi,Kojima,Hachiya,Hashimoto,Kawamura,Nakai,Toda
-
p. 299 - 301
(2007/10/03)
-
- Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer's γ-secretase: Implications for inhibitor design
-
The final step in the generation of the amyloid-β protein (Aβ), implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by γ-secretase. Although considered an important target for therapeutic design, γ-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state analogue inhibitors suggest that γ-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of γ-secretase, we prepared a series of difluoro ketone peptide analogues with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Aβ production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-butyl or cyclohexylmethyl, led to increased α-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-molecular-weight compound (50 ~ 5 μM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alcohol analogue with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that γ-secretase is an aspartyl protease. All new analogues inhibited total Aβ and Aβ42 production with the same rank order of potency and increased Aβ42 production at low concentrations, providing further evidence for distinct γ-secretases that are nevertheless closely similar with respect to active site topology and mechanism.
- Moore,Leatherwood,Diehl,Selkoe,Wolfe
-
p. 3434 - 3442
(2007/10/03)
-
- Synthesis of some pseudo-peptide analogs of thiol proteinase inhibitors
-
Some pseudo-peptide analogs of thiol proteinase inhibitors were synthesized by a conventional solution method. Among them, Suc-Ala-Val-Val- Ala-Ψ-(CH2-NH)-Ala-pNA (peptide 1) and Suc-Ala-Val-Val-Ψ-(CH2NH)-Ala- Ala-pNA (peptide 2) showed a stronger inhibitory activity compared with parent peptide such as Suc-Ala-Val-Val-Ala-Ala-pNA. In particular, peptide 2 was about 10-fold as active as the parent peptide (IC50=8 μM). Inserting Ψ-(CH2-NH) possibly makes the inhibitor less susceptible to papain and, as a result, pro-duces more potent inhibition.
- Iguchi, Shin,Kawasaki, Koichi,Okamoto, Hiroshi,Umezawa, Chisae,Okada, Yoshio
-
p. 423 - 427
(2007/10/03)
-
- γ-Peptides Forming More Stable Secondary Structures than α-Peptides: Synthesis and Helical NMR-Solution Structure of the γ-Hexapeptide Analog of H-(Val-Ala-Leu)2-OH
-
For a comparison with the corresponding α- and β-hexapeptides H-(Val-Ala-Leu)2-OH (A) and H-(β-HVal-β-HAla-β-HLeu)2-OH (B), we have now prepared the corresponding γ-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptanoic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Boc-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the γ-hexapeptide 1 (through the intermediate γ-di- and γ-tripeptide derivatives 9-11). Analysis of NMR measurements in (D5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the γ-hexapeptide 1 adopts a right-handed helical structure ((P)-2.61 helix of ca. 5-A pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding β-peptide B ((M)-31 helix of 5-A pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called α-helix of α-peptides ((P)-3.61 helix of 5.4-A pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from α- (N C) to β- (C N) to γ-peptides (N C). The surprising difference between the natural α-, and the analogous β- and γ-peptides is that the helix stability increases upon homologation of the residues.
- Hintermann, Tobias,Gademann, Karl,Jaun, Bernhard,Seebach, Dieter
-
p. 983 - 1002
(2007/10/03)
-
- A practical method for the combinatorial synthesis of peptide aldehydes
-
A practical strategy for solid phase synthesis of peptide aldehydes is described. An olefin linker is constructed using Wittig chemistry, after peptide synthesis ozonolytic treatment of the linker and subsequent workup with dimethyl sulphide results in fa
- Hall, Beverley J.,Sutherland, John D.
-
p. 6593 - 6596
(2007/10/03)
-
- CrCl2 mediated allylation of N-protected α-amino aldehydes. A versatile synthesis of polypeptides containing an hydroxyethylene isostere
-
Differently substituted allylic bromides react with N-protected amino aldehydes to give intermediate products for the synthesis of hydroxyethylene dipeptide isosteres. The low stereoselectivity of this reaction can be improved using aldehydes protected wi
- Ciapetti, Paola,Taddei, Maurizio,Ulivi, Paola
-
p. 3183 - 3186
(2007/10/02)
-
- Inhibition of human neutrophil elastase with peptidyl electrophilic ketones. 2. Orally active p(G)-Val-Pro-Val pentafluoroethyl ketones
-
Valylprolylvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lun
- Angelastro,Baugh,Bey,Burkhart,Chen,Durham,Hare,Huber,Janusz,Koehl,Marquart,Mehdi,Peet
-
p. 4538 - 4553
(2007/10/02)
-
- Inhibition of human leukocyte elastase by N-substituted peptides containing α,α-difluorostatone residues at P1
-
A series of tripeptides which contain α,α-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described cont
- Skiles,Miao,Sorcek,Jacober,Mui,Chow,Weldon,Possanza,Skoog,Keirns,Letts,Rosenthal
-
p. 4795 - 4808
(2007/10/02)
-
- A New Class of High Affinity Ligands for the Neurokinin A NK2 Receptor: ψ(CH2NR) Reduced Peptide Bond Analogues of Neurokinin A4-10
-
Analogues of 10>NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide ψ(CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to
- Harbeson, Scott L.,Shatzer, Scott A.,Le, Tieu-Binh,Buck, Stephen H.
-
p. 3949 - 3955
(2007/10/02)
-
- Efficient preparation of peptidyl pentaflouroethly ketones
-
A concise method for the preparation of α-amino pentafluoroethyl ketone salts from amino acids is described. These intermediates are useful for the preparation of peptidyl pentafluoroethyl ketones.
- Angeloastro, Michael R.,Burkhart, Joseph P.,Bey, Philippe,Peet, Norton P.
-
p. 3265 - 3268
(2007/10/02)
-
