- pDobz/pDobb protected diaminodiacid as a novel building block for peptide disulfide-bond mimic synthesis
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The diaminodiacid strategy has been widely studied in the chemical synthesis of peptide disulfide bond mimics. Diaminodiacid building blocks, which are key intermediates, are currently under the spotlight. However, one technical bottleneck inherent in existing building blocks is the contamination problem caused by the heavy metal reagents during the deprotection process, which makes the peptides less suitable for pharmaceutical use. Herein, we describe the successful development of a p-dihydroxyborylbenzyloxycarbonyl pinacol ester (pDobz)- and p-dihydroxyborylbenzyl pinacol ester (pDobb)-based novel diaminodiacid building block that can be easily deprotected via mild treatment with amine oxide. Its efficiency and practicability were also confirmed by the total synthesis of contryphan-Vn disulfide bond mimic. The results suggested that this novel diaminodiacid building block has satisfactory Fmoc SPPS compatibility, yet only required a facile, rapid, and metal-free deprotection process. We believe this novel diaminodiacid building block could promote further development of the diaminodiacid strategy.
- Liu, Chao,Zou, Yan,Hu, Honggang,Jiang, Yunyun,Qin, Luping
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p. 5438 - 5444
(2019/03/02)
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- Structure-based development of an osteoprotegerin-like glycopeptide that blocks RANKL/RANK interactions and reduces ovariectomy-induced bone loss in mice
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Osteoporosis is a metabolic bone disease characterized by low bone mass and micro-architectural deterioration of bone, for which the underlying mechanism is an imbalance between bone resorption and bone remodeling. The protein-protein interactions between receptor activator of nuclear factor-κB ligand (RANKL), RANK (its receptor), and osteoprotegerin (OPG), are known to mediate the development and activation of osteoclasts in bone remodeling, and are regarded as a pivotal therapeutic target for the treatment of osteoporosis. Herein, we disclose the successful development of a novel glycopeptide (OM-2), the structure of which is based on the key interacting sites of the reported RANKL and OPG crystal structure. OM-2 exhibited potent binding affinity with RANKL and resistance to degradation by protease enzymes. It also blocked RANKL/RANK interactions, and inhibited osteoclastogenesis in vitro. In vivo studies confirmed that OM-2 could effectively reduce bone loss and inhibit osteoclast activation in ovariectomized (OVX) mice at a dosage of 20.0 mg/kg/day. Accordingly, OM-2 is suggested as a therapeutic candidate for postmenopausal osteoporosis (PMOP) and osteoclastogenesis-related diseases like rheumatoid arthritis (RA). More importantly, its identification validates our structure-based strategy for the development of drugs that target the RANKL/RANK/OPG system.
- Liu, Chao,Chen, Xiao,Zhi, Xin,Weng, Weizong,Li, Quan,Li, Xiang,Zou, Yan,Su, Jiacan,Hu, Hong-Gang
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p. 661 - 672
(2018/01/19)
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- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
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The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
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p. 202 - 214
(2017/04/06)
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- Enantioselective Anion Recognition by Chiral Halogen-Bonding [2]Rotaxanes
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The application of chiral interlocked host molecules for discrimination of guest enantiomers has been largely overlooked, which is surprising given their unique three-dimensional binding cavities capable of guest encapsulation. Herein, we combined the stringent linear geometric interaction constraints of halogen bonding (XB), the noncovalent interaction between an electrophilic halogen atom and a Lewis base, with highly preorganized and conformationally restricted chiral cavities of [2]rotaxanes to achieve enantioselective anion recognition. Representing the first detailed investigation of the use of chiral XB rotaxanes for this purpose, extensive 1H NMR binding studies and molecular dynamics (MD) simulation experiments revealed that the chiral rotaxane cavity significantly enhances enantiodiscrimination compared to the non-interlocked free axle and macrocycle components. Furthermore, by examining the enantioselectivities of a family of structurally similar XB [2]rotaxanes containing different combinations of chiral and achiral macrocycle and axle components, the dominant influence of the chiral macrocycle in our rotaxane design for determining the effectiveness of chiral discrimination is demonstrated. MD simulations reveal the crucial geometric roles played by the XB interactions in orientating the bound enantiomeric anion guests for chiral selectivity, as well as the critical importance of the anions' hydration shells in governing binding affinity and enantiodiscrimination.
- Lim, Jason Y. C.,Marques, Igor,Félix, Vítor,Beer, Paul D.
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supporting information
p. 12228 - 12239
(2017/09/12)
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- Uracil-amino acid as a scaffold for β-sheet peptidomimetics: Study of photophysics and interaction with BSA protein
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We report herein the uracil-di-aza-amino acid (UrAA) as a new family of molecular scaffold to induce β-hairpin structure with H-bonded β-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine (TPyAlaDo and/or TMNapAlaDo) are embedded into two arms of the uracil-amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the β-hairpin structures for both the peptides. Study of photophysical property reveals that the pentapeptide containing fluorescent triazolyl unnatural amino acids TMNapAlaDo and TPyAlaDo at the two termini exhibits dual path entry to exciplex emission-either via FRET from TMNapAlaDo to TPyAlaDo or via direct excitation of a FRET acceptor, TPyAlaDo. The other pentapeptide with TPyAlaDo/TPyAlaDo pair shows excimer emission. Furthermore, both the peptides maintaining their fundamental photophysics are found to interact with BSA as only a test biomolecule.
- Bag, Subhendu Sekhar,Yashmeen, Afsana
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supporting information
p. 5387 - 5392
(2017/11/24)
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- Diaminodiacid-based synthesis of macrocyclic peptides using 1,2,3-triazole bridges as disulfide bond mimetics
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A new approach for the efficient construction of 1,2,3-triazole bridges as disulfide surrogates in peptides, utilizing the diaminodiacid strategy was established. Two thanatin derivatives were prepared with 1,5- and 1,4-disubstituted 1,2,3-triazole diaminodiacids as building blocks. The antibacterial activity studies are also described here.
- Guo, Ye,Liu, Chao,Song, Hui,Wang, Feng-Liang,Zou, Yan,Wu, Qiu-Ye,Hu, Hong-Gang
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p. 2110 - 2114
(2017/01/21)
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- Simple preparation of new [18F]F-labeled synthetic amino acid derivatives with two click reactions in one-pot and SPE purification
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New [18F]fluorinated 1,2,3-triazolyl amino acid derivatives were efficiently prepared from Huisgen 1,3-dipolar cycloaddition reactions, well known as click reaction. We developed two simultaneous click reactions in one-pot with a simple solid-p
- Yook, Cheol-Min,Lee, Sang Ju,Oh, Seung Jun,Ha, Hyun-Joon,Lee, Jong Jin
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p. 317 - 326
(2015/08/03)
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- Triazolo-β-aza-ε-amino acid and its aromatic analogue as novel scaffolds for β-turn peptidomimetics
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Triazolo-β-aza-ε-amino acid and its aromatic analogue (AlTAA/ArTAA) in the peptide backbone mark a novel class of conformationally constrained molecular scaffolds to induce β-turn conformations. This was demonstrated forAlTAA in a Leu-enkephalin analogue and in a designed pentapeptide wherein the FRET process was established. Restricted rotation induced chirality and turn conformation into the achiral aromatic amino acid scaffold,ArTAA, which in a short tripeptide backbone acted as a β-turn mimic as a β-sheet folding nucleator. This journal is
- Bag, Subhendu Sekhar,Jana, Subhashis,Yashmeen, Afsana,De, Suranjan
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supporting information
p. 5242 - 5245
(2015/03/30)
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- Clickable Cγ-azido(methylene/butylene) peptide nucleic acids and their clicked fluorescent derivatives: Synthesis, DNA hybridization properties, and cell penetration studies
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Synthesis, characterization, and DNA complementation studies of clickable Cγ-substituted methylene (azm)/butylene (azb) azido PNAs show that these analogues enhance the stability of the derived PNA:DNA duplexes. The fluorescent PNA oligomers synthesized by their click reaction with propyne carboxyfluorescein are seen to accumulate around the nuclear membrane in 3T3 cells.
- Jain, Deepak R.,Ganesh, Krishna N.
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p. 6708 - 6714
(2014/08/05)
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- Cyclic RGD peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands
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The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins αvβ 3 and αvβ5, which are involved in tumor angiogenesis. Nanomolar IC50 values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by 1H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [Cβ(Arg)-Cβ(Asp) average distance ≥8.8 A]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin αvβ3 complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex. Copyright
- Marchini, Mattia,Mingozzi, Michele,Colombo, Raffaele,Guzzetti, Ileana,Belvisi, Laura,Vasile, Francesca,Potenza, Donatella,Piarulli, Umberto,Arosio, Daniela,Gennari, Cesare
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supporting information; scheme or table
p. 6195 - 6207
(2012/06/18)
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- Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3
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A small library of integrin ligand-paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified αVβ3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin αVβ3, making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.
- Colombo, Raffaele,Mingozzi, Michele,Belvisi, Laura,Arosio, Daniela,Piarulli, Umberto,Carenini, Nives,Perego, Paola,Zaffaroni, Nadia,De Cesare, Michelandrea,Castiglioni, Vittoria,Scanziani, Eugenio,Gennari, Cesare
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supporting information
p. 10460 - 10474
(2013/02/22)
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- New β-strand templates constrained by Huisgen cycloaddition
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New peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P1 and P3 residues of a tripeptide by Huisgen cycloaddition are presented. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions that should be suitable for targeting a range of proteases and other applications requiring such a geometry.
- Pehere, Ashok D.,Abell, Andrew D.
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supporting information; experimental part
p. 1330 - 1333
(2012/05/20)
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- Solid-phase total synthesis of (-)-apratoxin a and its analogues and their biological evaluation
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Two approaches for the solid-phase total synthesis of apratoxinA and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer-support, macrolactamization of 10, followed by thiazoline formation, provided apratoxinA. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid-phase peptide synthesis by using amino acids 13-15 and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxinA, and O-methyl tyrosine can be replaced by 7-azidoheptyl tyrosine without loss of activity. The 1,3-dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring. Solid Approach: Two routes for the solid-phase total synthesis of apratoxinA have been described. On the basis of this method, its analogues were synthesized and their biological activity has been evaluated. Copyright
- Doi, Takayuki,Numajiri, Yoshitaka,Takahashi, Takashi,Takagi, Motoki,Shin-Ya, Kazuo
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supporting information; experimental part
p. 180 - 188
(2011/10/08)
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- Fmoc-chemistry of a stable phosphohistidine analogue
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We report the synthesis of the phosphohistidine analogue, Fmoc-4-diethylphosphonotriazolylalanine 5 and its incorporation into peptides. Our synthesis of 5 has enabled us to demonstrate that the analogue is compatible with Fmoc-solid phase peptide synthesis (SPPS) conditions. Standard cleavage conditions yield the diethyl phosphonate-protected peptide, however this can be subsequently deprotected using trimethylsilyl bromide to yield the free phosphonic acid-containing peptides.
- McAllister, Tom E.,Nix, Michael G.,Webb, Michael E.
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supporting information; experimental part
p. 1297 - 1299
(2011/03/20)
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- Synthesis and evaluation of bombesin analogues conjugated to two different triazolyl-derived chelators for 99mTc labeling
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Overexpression of the gastrin-releasing peptide receptor (GRPR) in a variety of human carcinomas has provided a means of diagnosis and treatment. Previously we reported a metabolically stable (NαHis)Ac-βAla- βAla-[Cha13,Nle14]BBS(7-14) analogue with high affinity for the GRPR. We have also shown that the biodistribution pattern of this fairly lipophilic, radiolabeled peptide can be enhanced by glycation, which is easily carried out by CuI-catalyzed cycloaddition. Herein, we further elaborate this "click approach" in the synthesis of a new series of triazole-based chelating systems as alternatives to the (NHis)Ac chelator for labeling with the 99mTc(CO)3 core. The bombesin analogues, containing these new chelating systems, were evaluated with regard to their synthesis and in vitro and in vivo properties, and were compared with their (NαHis)Ac counterparts. The influence of the chelator on biodistribution properties was less than that of glycation, which clearly improved the tumor-to-background ratios. 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
- Brans, Luc,Garcia-Garayoa, Elisa,Schweinsberg, Christian,Maes, Veronique,Struthers, Harriet,Schibli, Roger,Tourwe, Dirk
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experimental part
p. 1717 - 1725
(2012/01/04)
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- 1,2,3-Triazolyl amino acids as AMPA receptor ligands
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The central nervous system glutamate receptors are an important target for drug discovery. Herein we report initial investigations into the synthesis and glutamate receptor activity of 1,2,3-triazolyl amino acids. Two compounds were found to be selective
- Stanley,Pedersen, D. Sejer,Nielsen,Kvist,Mathiesen,Br?uner-Osborne,Taylor,Abell
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supporting information; experimental part
p. 7512 - 7515
(2011/03/17)
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- A short synthetic approach to chiral serine azido derivatives
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We report a new synthetic methodology for the synthesis of chiral serine azido derivatives through a conversion of N-protected (Boc, Cbz and Fmoc) serine amino acid into its corresponding Weinreb amide. Thus, acidity of the α-proton of the serine is reduced and it allows nucleophilic addition reaction onto Weinreb amide to furnish chiral serine azido derivatives.
- Panda, Gautam,Rao, N. Venugopal
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p. 714 - 716
(2007/10/03)
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- Assembling heterocycle-tethered C-glycosyl and α-amino acid residues via 1,3-dipolar cycloaddition reactions
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(Equation Presented) The 1,3-dipolar cycloadditions of C-glycosyl nitrile oxides and acetylenes to an alkyne and an azide, respectively, bearing a masked glycinyl moiety furnished disubstituted isoxazoles and triazoles. Unveiling the glycinyl group in the
- Dondoni, Alessandro,Giovannini, Pier Paolo,Massi, Alessandro
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p. 2929 - 2932
(2007/10/03)
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- Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides
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A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N- terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 ± 4%) is the highest reported for any peptidic renin inhibitor.
- Rosenberg,Spina,Woods,Polakowski,Martin,Yao,Stein,Cohen,Barlow,Egan,Tricarico,Baker,Kleinert
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p. 449 - 459
(2007/10/02)
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