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Cyclic isoDGR and RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds are Integrin Antagonists 下载免费PDF全文
Silvia Panzeri Simone Zanella Dr. Daniela Arosio Leila Vahdati Alberto Dal Corso Dr. Luca Pignataro Dr. Mayra Paolillo Prof. Dr. Sergio Schinelli Prof. Dr. Laura Belvisi Prof. Dr. Cesare Gennari Prof. Dr. Umberto Piarulli 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(16):6265-6271
The cyclo[DKP‐isoDGR] peptidomimetics 2 – 5 , containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αvβ3 and αvβ5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3 ) to submicromolar with αvβ3 integrin. The biological activities of ligands cyclo[DKP3‐RGD] 1 and cyclo[DKP3‐isoDGR] 3 , bearing the same bifunctional DKP scaffold and showing similar αVβ3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin‐mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment. 相似文献
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Christos Liolios Christos Sachpekidis Antonios Kolocouris Antonia Dimitrakopoulou-Strauss Penelope Bouziotis 《Molecules (Basel, Switzerland)》2021,26(6)
Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F, 64Cu, and 68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included. 相似文献
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Andrea Sartori Kelly Bugatti Elisabetta Portioli Monica Baiula Irene Casamassima Agostino Bruno Francesca Bianchini Claudio Curti Franca Zanardi Lucia Battistini 《Molecules (Basel, Switzerland)》2021,26(19)
Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds. 相似文献
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《Chemical record (New York, N.Y.)》2018,18(3):266-281
Fluorine‐containing organic molecules have generated increasing impact in drug research over the past decade. Their preparation and development of novel synthetic methods towards new types of fluorinated molecules among them of β‐amino acid derivatives has received large interest. Our research group have designed various highly selective and stereocontrolled methods for the construction of fluorine‐containing cyclic β‐amino acid derivatives. The synthetic approaches developed for the synthesis of various pharmacologically interesting cyclic β‐amino acid derivatives as monomers with multiple stereogenic centers might be valuable protocols for the access of other classes of organic compounds. 相似文献
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Synthesis and Analysis of the Conformational Preferences of 5‐Aminomethyloxazolidine‐2,4‐dione Scaffolds: First Examples of β2‐ and β2, 2‐Homo‐Freidinger Lactam Analogues 下载免费PDF全文
Arianna Greco Sara Tani Rossella De Marco Luca Gentilucci 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(41):13390-13404
Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single‐step cyclization of (S)‐ or (R)‐α‐hydroxy‐β2‐ or α‐substituted‐α‐hydroxy‐β2, 2‐amino acids already incorporated within oligopeptides to 5‐aminomethyl‐oxazolidine‐2,4‐dione (Amo) rings. These scaffolds can be regarded as unprecedented β2‐ or β2, 2‐homo‐Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi‐bent or folded geometries, depending on the relative stereochemistry and the presence of α‐substituents. 相似文献
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Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6‐Selective Integrin Ligands 下载免费PDF全文
Dr. Oleg V. Maltsev Dr. Udaya Kiran Marelli Tobias G. Kapp Dr. Francesco Saverio Di Leva Dr. Salvatore Di Maro Dr. Markus Nieberler Prof. Dr. Ute Reuning Prof. Dr. Markus Schwaiger Prof. Dr. Ettore Novellino Prof. Dr. Luciana Marinelli Prof. Dr. Horst Kessler 《Angewandte Chemie (International ed. in English)》2016,55(4):1535-1539
The αvβ6 integrin binds the RGD‐containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub‐nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide. Finally, the utility of the ligand for use in biomedical studies was also demonstrated here. 相似文献
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Dr. Richard J. D. Hatley Dr. Simon J. F. Macdonald Dr. Robert J. Slack Dr. Joelle Le Dr. Steven B. Ludbrook Dr. Pauline T. Lukey 《Angewandte Chemie (International ed. in English)》2018,57(13):3298-3321
There is a requirement for efficacious and safe medicines to treat diseases with high unmet need. The resurgence in αv‐RGD integrin inhibitor drug discovery is poised to contribute to this requirement. However, drug discovery in the αv integrin space is notoriously difficult due to the receptors being structurally very similar as well as the polar zwitterionic nature of the pharmacophore. This Review aims to guide drug discovery research in this field through an αv inhibitor toolbox, consisting of small molecules and antibodies. Small‐molecule αv tool compounds with extended profiles in αvβ1, 3, 5, 6 and 8 cell adhesion assays, with key physicochemical properties, have been collated to assist in the selection of the right tool for the right experiment. This should also facilitate an understanding of partial selectivity profiles of compounds generated in different assays across research institutions. Prospects for further αv integrin research and the critical importance of target validation are discussed, where increased knowledge of the selectivity for individual RGD αv integrins is key. Insights into the design of small‐molecule RGD chemotypes for topical or oral administration are provided and clinical findings on advanced molecules are examined. 相似文献
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Dr. Biancamaria Farina Dr. Ivan de Paola Dr. Luigi Russo Dr. Domenica Capasso Dr. Annamaria Liguoro Dr. Annarita Del Gatto Dr. Michele Saviano Prof. Paolo V. Pedone Dr. Sonia Di Gaetano Dr. Gaetano Malgieri Dr. Laura Zaccaro Prof. Roberto Fattorusso 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(2):681-693
The critical role of integrins in tumor progression and metastasis has stimulated intense efforts to identify pharmacological agents that can modulate integrin function. In recent years, αvβ3 and αvβ5 integrin antagonists were demonstrated to be effective in blocking tumor progression. RGDechi‐hCit, a chimeric peptide containing a cyclic RGD motif linked to an echistatin C‐terminal fragment, is able to recognize selectively αvβ3 integrin both in vitro and in vivo. High‐resolution molecular details of the selective αvβ3 recognition of the peptide are certainly required, nonetheless RGDechi‐hCit internalization limited the use of classical in cell NMR experiments. To overcome such limitations, we used WM266 isolated cellular membranes to accomplish a detailed NMR interaction study that, combined with a computational analysis, provides significant structural insights into αvβ3 molecular recognition by RGDechi‐hCit. Remarkably, on the basis of the identified molecular determinants, we design a RGDechi‐hCit mutant that is selective for αvβ5 integrin. 相似文献
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Dominik Heckmann Dr. Burkhardt Laufer M. Sc. Luciana Marinelli Prof. Dr. Vittorio Limongelli Dr. Ettore Novellino Prof. Dr. Grit Zahn Dr. Roland Stragies Dr. Horst Kessler Prof. Dr. 《Angewandte Chemie (International ed. in English)》2009,48(24):4436-4440
A suitable substitute : All integrin receptors bind their ligands, which contain an aspartate residue, in the metal‐ion‐ dependent adhesion site (MIDAS). So far all attempts to replace the carboxyl group of aspartate with other, pharmacologically favorable isosteric groups have failed. Now it has been shown that a hydroxamic acid group can replace the carboxyl group; the resulting ligand retains its high binding activity. The picture shows one such ligand in the binding site of αvβ3.
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《Angewandte Chemie (International ed. in English)》2017,56(51):16405-16409
A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N‐methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N‐methylated analogues of the stem peptide cyclo(d ‐Ala‐Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD‐recognizing integrin subtypes; 5) fine‐tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration. 相似文献
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A novel β‐diketiminato ligand precursor, LH ( II ), containing thioether tethers was synthesized by the reaction of acetylacetone and 2‐methylthioaniline. II was deprotonated and used in the synthesis of two iron(II) complexes, [LFeCl] ( 1 ), and [LFeOTf] ( 2 ), and one nickel(II) complex, [LNiBr] ( 3 ). All three compounds were characterized by means of single crystal X‐ray diffraction and their structures are discussed. 相似文献
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Andreas Grauer Andreas Späth Dawei Ma Prof. Dr. Burkhard König Prof. Dr. 《化学:亚洲杂志》2009,4(7):1134-1140
Making circles with N and O : Cyclic tripeptides containing an unnatural Cα‐tetrasubstituted THF amino acid are prepared by copper(I) and palladium(0)‐catalyzed N‐ and O‐arylation reactions. The reactions give access to side chain‐modified derivatives of the unnatural amino acid and macrocyclic peptidomimetics.