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Gerald Pattenden - One of the best experts on this subject based on the ideXlab platform.
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Novel polyoxazole-based Cyclopeptides from Streptomyces sp. Total synthesis of the Cyclopeptide YM-216391 and synthetic studies towards telomestatin
Organic & biomolecular chemistry, 2008Co-Authors: Jon Deeley, Anna Bertram, Gerald PattendenAbstract:A convergent, complementary, synthetic approach to the contiguously linked tris-oxazole units 10, 11 and 12 in telomestatin (1) and YM-216391 (2) is described. The route involves coupling reactions between oxazole 4-carboxylic acids, viz16a, 16c, 16d and oxazole 2-substituted methylamines, viz16b, 16e, 17, leading to the amides 18 and 21, followed by cyclodehydrations to the corresponding bis-oxazole oxazolines, e.g.19, and oxidations of the latter using well-established protocols. The tris-oxazoles 11 and 12 were next converted stepwise into the hexa-oxazole bis-macrolactams 33. Although the bis-macrolactams 33 (cf.28) could be converted into the corresponding oxazoline-hexa-oxazoles 34 and to the enamides 35, neither of these intermediates could be elaborated to the hepta-oxazole 30en route to telomestatin 1. Likewise, neither the hexa-oxazole 47 or application of an intramolecular Hantzsch oxazole ring-forming reaction from 44b allowed access to the advanced polyoxazole-macrolactam intermediates 48 and 30a, respectively, towards telomestatin. Combination of the tris-oxazole based methylamine 70 with the dipeptide carboxylic acid 71 derived from D-valine and L-isoleucine, leads to the corresponding amide which, in two straightforward steps, is converted into the ω-amino acid 78. Macrolactamisation of 78, using HATU, next produces the Cyclopeptide 79 which is then elaborated to the thiazole and oxazole based Cyclopeptide YM-216391 (2). The synthetic Cyclopeptide 2 is shown to be the enantiomer of the natural product isolated from Streptomyces nobilis.
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synthesis and establishment of stereochemistry of the unusual polyoxazole thiazole based Cyclopeptide ym 216391 isolated from streptomyces nobilis
Chemical Communications, 2005Co-Authors: Jon Deeley, Gerald PattendenAbstract:A concise total synthesis of the unusual oxazole-based Cyclopeptide structure YM-216391, which also establishes the stereochemistry of the natural product i.e.1, is described.
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total synthesis and assignment of configuration of the thiazoline based Cyclopeptide cyclodidemnamide isolated from the sea squirt didemnum molle
Journal of The Chemical Society-perkin Transactions 1, 2000Co-Authors: Christopher D J Boden, Mark Norley, Gerald PattendenAbstract:A total synthesis of the proposed structure 1 for the oxazoline/thiazoline-based Cyclopeptide cyclodidemnamide, isolated from the sea squirt Didemnum molle, is described. The synthesis features a novel double cyclodehydration, sequential formation of chiral thiazoline and oxazoline rings in a preformed Cyclopeptide intermediate, as a key stratagem. The NMR spectroscopic data for synthetic 1 and natural cyclodidemnamide did not correlate. The configuration of the natural product was re-assigned as 15, the C-15-(R)-Val epimer, which was confirmed by total synthesis.
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total synthesis and revision of stereochemistry of cyclodidemnamide a novel Cyclopeptide from the marine ascidian didemnum molle
Tetrahedron Letters, 1998Co-Authors: Mark Norley, Gerald PattendenAbstract:Abstract A total synthesis establishes the structure and stereochemistry of the novel heterocycle-based Cyclopeptide cyclodidemnamide isolated from the “sea squirt” Didemnum molle as 1b , not 1a .
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Marine metabolites and metal ion chelation. Circular dichroism studies of metal binding to Lissoclinum Cyclopeptides
Journal of the Chemical Society Perkin Transactions 2, 1998Co-Authors: David J. Freeman, Gerald Pattenden, Alex F. Drake, Giuliano SiligardiAbstract:Variable temperature circular dichroism (CD) spectra of the patellamides A (3), B (4) and E (5), isolated from the ascidian (‘sea squirt’) Lissoclinum patella, show that they have very similar thermodynamically preferred macrocyclic ring conformations. In addition, the CD profile of the ‘figure eight like’ conformation 10 in the patellamides has been defined, and CD spectroscopy is shown to provide an insight into the interconversions between the limiting conformations, 9 and 10, in this family of Cyclopeptides. The Cyclopeptides 3–5 bind both Cu2+ and Zn2+ and CD studies show that as a family, in line with previous studies, they can bind more than one metal ion per molecule. Thus, the first binding domain for the three patellamides shows a binding constant in the range 2 × 104 to 2 × 105, and a second binding site for patellamide B (4) has K = 230 (Cu2+) and K = 16–20 (Zn2+). The CD spectra of the patellamide–metal conjugates can be correlated with the ‘square form’ conformation 9 of the Cyclopeptides. This best fit situation vis-a-vis metal chelation, could have important implications regarding the biological activity and modus operandi of the Cyclopeptides in vivo.
Ninghua Tan - One of the best experts on this subject based on the ideXlab platform.
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rubipodanin a the first natural n desmonomethyl rubiaceae type Cyclopeptide from rubia podantha indicating an important role of the n9 methyl group in the conformation and bioactivity
PLOS ONE, 2015Co-Authors: Zhe Wang, Guang-zhi Zeng, Ninghua Tan, Si-meng Zhao, Limei Zhao, Xiaoqiang ChenAbstract:One new cyclic hexapeptide named rubipodanin A (1), which is the first identified natural N-desmonomethyl Rubiaceae-type Cyclopeptide, together with six known Rubiaceae-type Cyclopeptides (2-7) were obtained using the TLC Cyclopeptide protosite detection method with ninhydrin from the roots and rhizomes of Rubia podantha. The Cyclopeptide structures were elucidated by extensive spectroscopic analysis, including 1D-NMR, 2D-NMR, IR, UV and MS. The solution conformation and biological activities of 1 and RA-V (4) were evaluated, and the results demonstrated that the N-9-methyl group plays a vital role in the maintenance of the conformation and bioactivity.
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chemical progress in Cyclopeptide containing traditional medicines cited in chinese pharmacopoeia
Chinese Journal of Chemistry, 2012Co-Authors: Si-meng Zhao, Bin Kuang, Wenwen Peng, Jing Han, Yuqing Zheng, Weiwu Song, Ninghua TanAbstract:Plant Cyclopeptides, cyclic compounds formed mainly by the peptidic bonds of 237 protein and non-protein amino acids (mainly L-amino acids) and found in higher plants, have been attractive for their extensive bioactivities and distinctive molecular architectures. During the last half century's study, about 500 Cyclopeptides divided into eight types have been isolated from over 120 species, which belong to over 20 families and 60 genera. Some Cyclopeptides showed potential anti-tumor, sedative, immunosuppressive, and uterotonic activities. In the Chinese Pharmacopoeia (CP, 2010 Version), 23 species (14 families, 18 genera) containing Cyclopeptides have been recorded in the origins of 24 traditional Chinese medicines (TCMs). Heterophyllin B (64), first reported by us from Pseudostellaria heterophylla in 1993 was cited for the first time in CP as the standard substance of Cyclopeptides for quality control. In this review, we highlight the progress in the chemical studies of these Cyclopeptide-containing TCMs, in particular recent results in our group's publications.
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Cyclopeptides from Rubia schumanniana
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 2012Co-Authors: Bin Kuang, Jun-ting Fan, Si-meng Zhao, Ninghua TanAbstract:OBJECTIVE To separate and identify Cyclopeptides of tubers of Rubia schumanniana. METHOD The 70% methanol extracts from tubers of Rubia schumanniana were separated and purified by silica gel, RP-18, Sephedax LH-20 and HPLC. Their structures were identified by spectral analysis. RESULT Nine Cyclopeptides were separated and identified as RA- II (1), RA-V (2), RA-VIII (3), rubiyunnanin C (4), RA-X (5), RY-II (6), RA- I (7), RA-XIII (8) and RA-XIII-OMe (9), respectively. CONCLUSION All of nine Cyclopeptides were separated from R. schumanniana for the first time.
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An in vitro system to study Cyclopeptide heterophyllin B biosynthesis in the medicinal plant Pseudostellaria heterophylla
Plant Cell Tissue and Organ Culture (PCTOC), 2011Co-Authors: Hongtao Zhu, Jun Tang, Ninghua Tan, Ying-jun Zhang, Ronald L. CernyAbstract:Plant Cyclopeptides are a large group of small molecule metabolites found in a wide variety of plants, including traditional Chinese medicinal plants. Many of the Cyclopeptides have highly unusual structures and potent biological activities. However, the majority of the Cyclopeptides have not been studied for their biosynthetic mechanisms. In this study, we have established a culture system for the biosynthetic study of heterophyllin B (HB), a Cyclopeptide produced by the medicinal plant Pseudostellaria heterophylla. We first developed a shoot culture of P. heterophylla that produced HB consistently under laboratory conditions. Using 14C-labeled proline as tracer, we showed that labeled HB was produced by the cultured shoots, indicating that this system has de novo biosynthetic activity. Next, we chemically synthesized HB’s linear peptide precursor (LHB) and the N-acetyl cysteamine thioester of LHB (LHB-SNAC). When LHB-SNAC was incubated with total cell free extracts of the cultured shoots, a small amount of cyclized product (HB), in addition to the hydrolyzed product (LHB), was produced. The in vivo and in vitro results demonstrate the presence of an HB biosynthetic system, which provides insight into the molecular mechanism for plant Cyclopeptide biosynthesis.
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Various mechanisms in Cyclopeptide production from precursors synthesized independently of non-ribosomal peptide synthetases.
Acta biochimica et biophysica Sinica, 2011Co-Authors: Ninghua TanAbstract:An increasing number of Cyclopeptides have been discovered as products of ribosomal synthetic pathway. The biosynthetic study of these Cyclopeptides has revealed interesting new mechanisms for cyclization. This review highlighted the recent discoveries in cyclization mechanisms for Cyclopeptides synthesized independently of non-ribosomal peptide synthetases, including endopeptidase-catalyzed cyclization, intein-mediated cyclization, and peptide synthetase-catalyzed cyclization. This information may help to design hybrid ribosomal and non-ribosomal biosynthetic systems to produce novel Cyclopeptides with various bioactivities.
Stefan Kubik - One of the best experts on this subject based on the ideXlab platform.
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Anion Recognition in Aqueous Media by Cyclopeptides and Other Synthetic Receptors
Accounts of chemical research, 2017Co-Authors: Stefan KubikAbstract:ConspectusAnion receptors often rely on coordinative or multiple ionic interactions to be active in water. In the absence of such strong interactions, anion binding in water can also be efficient, however, as demonstrated by a number of anion receptors developed in recent years. The Cyclopeptide-derived receptors comprising an alternating sequence of l-proline and 6-aminopicolinic acid subunits are an example. These Cyclopeptides are neutral and, at first sight, can only engage in hydrogen-bond formation with an anionic substrate. Nevertheless, they even interact with strongly solvated sulfate anions in water. The intrinsic anion affinity of these Cyclopeptides can be related to structural aspects of their highly preorganized concave binding site, which comprises a wall of hydrophobic proline units arranged around the peptide NH groups at the cavity base. When anions are incorporated into this cavity they can engage in hydrogen-bonding interactions to the NH groups, and complex formation also benefits fro...
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Effects of Solvent Properties on the Anion Binding of Neutral Water-Soluble Bis(Cyclopeptides) in Water and Aqueous Solvent Mixtures
2017Co-Authors: Fabian Sommer, Yizhak Marcus, Stefan KubikAbstract:In this study, the anion-binding bis(Cyclopeptide) 2 is introduced, which dissolves freely in water, affording up to 10 mM concentrations, thanks to triethylene glycol-derived substituents in the Cyclopeptide subunits and the linker connecting them. Binding studies provided evidence that the anion affinity previously demonstrated for less-soluble analogs of this compound is retained under highly competitive aqueous conditions. The highest affinity in water was observed for iodide, closely followed by sulfate anions, whereas binding of soft and weakly coordinating anions could not be observed. The anion selectivity of 2 thus differs from that of other recently described receptors, which also do not require electrostatic or coordinative interactions for anion binding in water but typically fail to bind strongly coordinating sulfate anions. The ability of 2 to overcome sulfate hydration is attributed to the special mode of binding, combining direct N–H···A– interactions with the release of water molecules from the receptor cavity. The characterization of the anion binding of 2 and a related bis(Cyclopeptide) in a variety of different solvents and aqueous solvent mixtures furthermore allowed the correlation of the binding properties with solvent parameters. These analyses provided qualitative and even quantitative insights into the solvent properties and solvation phenomena that mainly affect anion complexation
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a Cyclopeptide derived molecular cage for sulfate ions that closes with a click
Chemistry: A European Journal, 2010Co-Authors: Thomas Fiehn, Richard Goddard, Rüdiger W. Seidel, Stefan KubikAbstract:The 2:1 sandwich-type complexes formed between a Cyclopeptide with alternating L -proline and 6-amino-picolinic acid subunits and inorganic anions can be stabilized by covalently linking a tris-alkyne and a tris-azide derivative of this peptide through copper-catalyzed azide-alkyne cycloaddition. The resulting triply linked bis-Cyclopeptide can interact with anions such as sulfate ions in aqueous solution by including them into the cavity between the two Cyclopeptide rings, where they can form hydrogen bonds to amide NH groups, distributed along the inner surface. The binding kinetics of this system differ significantly from those of a bis-Cyclopeptide that contains only one linker because the rate of guest exchange is considerably slower. Thermodynamically, the stability of the sulfate complex of the triply linked bis-Cyclopeptide approaches a log K a value of 6 in H 2 O/CH 3 OH 1:1 (v/v) which is, however, only approximately one order of magnitude larger than affinity of the more flexible monolinked analogue. Titration calorimetry revealed that this behavior is mainly due to the change in the binding enthalpy from exothermic to endothermic upon increasing the number of linkers. Results from NMR spectroscopy and X-ray crystallography indicate that the mono- and triply linked bis-Cyclopeptides adopt similar conformations in their complexes with sulfate ions, but the complex formation is enthalpically unfavorable for the cage. The substantial entropic contribution to sulfate complexation of this receptor more than compensates for this disadvantage, so that the overall sulfate affinity of both bis-Cyclopeptides ends up in the same range. These investigations provide important insight into the structure-property relationships of such receptors, thus leading the way to further structural improvement.
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A Cyclopeptide‐Derived Molecular Cage for Sulfate Ions That Closes with a Click
Chemistry (Weinheim an der Bergstrasse Germany), 2010Co-Authors: Thomas Fiehn, Richard Goddard, Rüdiger W. Seidel, Stefan KubikAbstract:The 2:1 sandwich-type complexes formed between a Cyclopeptide with alternating L -proline and 6-amino-picolinic acid subunits and inorganic anions can be stabilized by covalently linking a tris-alkyne and a tris-azide derivative of this peptide through copper-catalyzed azide-alkyne cycloaddition. The resulting triply linked bis-Cyclopeptide can interact with anions such as sulfate ions in aqueous solution by including them into the cavity between the two Cyclopeptide rings, where they can form hydrogen bonds to amide NH groups, distributed along the inner surface. The binding kinetics of this system differ significantly from those of a bis-Cyclopeptide that contains only one linker because the rate of guest exchange is considerably slower. Thermodynamically, the stability of the sulfate complex of the triply linked bis-Cyclopeptide approaches a log K a value of 6 in H 2 O/CH 3 OH 1:1 (v/v) which is, however, only approximately one order of magnitude larger than affinity of the more flexible monolinked analogue. Titration calorimetry revealed that this behavior is mainly due to the change in the binding enthalpy from exothermic to endothermic upon increasing the number of linkers. Results from NMR spectroscopy and X-ray crystallography indicate that the mono- and triply linked bis-Cyclopeptides adopt similar conformations in their complexes with sulfate ions, but the complex formation is enthalpically unfavorable for the cage. The substantial entropic contribution to sulfate complexation of this receptor more than compensates for this disadvantage, so that the overall sulfate affinity of both bis-Cyclopeptides ends up in the same range. These investigations provide important insight into the structure-property relationships of such receptors, thus leading the way to further structural improvement.
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Selective sensing of sulfate in aqueous solution using a fluorescent bis(Cyclopeptide).
Organic letters, 2007Co-Authors: Carsten Reyheller, Stefan KubikAbstract:Fluorescence of a bis(Cyclopeptide) in which two cyclohexapeptide moieties with alternating l-proline and 6-aminopicolinic acid subunits are attached to a 4,4‘-bis(dimethylamino)biphenyl linker is quenched in 1:1 (v/v) water/methanol in the presence of sulfate. Of eight other anions tested, none produced a similar effect. This bis(Cyclopeptide) allows the qualitative and quantitative detection of sulfate even in the presence of an excess of chloride anions. Calculations provided insight into the causes of fluorescence quenching and anion selectivity.
François-xavier Maquart - One of the best experts on this subject based on the ideXlab platform.
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The YSNSG Cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration.
International Journal of Cancer Supplement, 2010Co-Authors: Jessica Thevenard, Laurent Ramont, Jérome Devy, Bertrand Brassart, Aurélie Dupont-deshorgue, Nicolas Floquet, Laurence Schneider, Farid Ouchani, Christine Terryn, François-xavier MaquartAbstract:We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a β-turn crucial for biological activity. More recently, a YSNSG Cyclopeptide with a constrained β-turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG Cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG Cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG Cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1-MMP at the migration front as well as a decrease in u-PA and u-PAR expression. The Cyclopeptide also altered β1-integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125FAK), disorganized F-actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG Cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity.
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The YSNSG Cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration
International Journal of Cancer, 2009Co-Authors: Jessica Thevenard, Laurent Ramont, Jérome Devy, Bertrand Brassart, Aurélie Dupont-deshorgue, Nicolas Floquet, Laurence Schneider, Farid Ouchani, Christine Terryn, François-xavier MaquartAbstract:International audienceWe previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a β-turn crucial for biological activity. More recently, a YSNSG Cyclopeptide with a constrained β-turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG Cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG Cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG Cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1-MMP at the migration front as well as a decrease in u-PA and u-PAR expression. The Cyclopeptide also altered β1-integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125FAK), disorganized F-actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG Cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity
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Structural and antitumor properties of the YSNSG Cyclopeptide derived from tumstatin.
Chemistry & biology, 2006Co-Authors: Jessica Thevenard, Laurent Ramont, Nicolas Floquet, François-xavier Maquart, Elise Prost, Jean-marc Nuzillard, Manuel Dauchez, Hocine Yezid, Alain J. P. Alix, Jean-claude MonboisseAbstract:Summary We previously demonstrated that the NC1[α3(IV)185–191] CNYYSNS peptide inhibited in vivo tumor progression. The YSNS motif formed a β turn crucial for biological activity. The aim of the present study was to design a YSNSG Cyclopeptide with a constrained β turn on the YSNS residues more stable than CNYYSNS. By nuclear magnetic resonance and molecular modeling, we demonstrated that the YSNSG Cyclopeptide actually adopted the expected β-turn conformation. It promoted melanoma cell adhesion and prevented their adhesion to the native peptide. It inhibited in vitro cell proliferation and migration through Matrigel by downregulating proteolytic cascades. Moreover, intraperitoneal administration of the YSNSG Cyclopeptide inhibited melanoma progression far more efficiently than the native peptide. The increased solubility and stability at low pH of the YSNSG Cyclopeptide suggest this peptide as a potent antitumor therapeutic agent.
Flavio Curnis - One of the best experts on this subject based on the ideXlab platform.
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succinimide based conjugates improve isodgr Cyclopeptide affinity to αvβ3 without promoting integrin allosteric activation
Journal of Medicinal Chemistry, 2018Co-Authors: Francesca Nardelli, Cristina Paissoni, Giacomo Quilici, Alessandro Gori, Catia Traversari, Barbara Valentinis, Angelina Sacchi, Angelo Corti, Flavio CurnisAbstract:The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that Cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-(N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various Cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved ...
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Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αvβ3 without Promoting Integrin Allosteric Activation
2018Co-Authors: Francesca Nardelli, Cristina Paissoni, Giacomo Quilici, Alessandro Gori, Catia Traversari, Barbara Valentinis, Angelina Sacchi, Angelo Corti, Flavio Curnis, Michela GhittiAbstract:The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that Cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-(N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αvβ3, an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various Cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce αvβ3 allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved αvβ3-binding properties and devoid of adverse integrin-activating effects
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Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to( )alpha(v)beta(3) without Promoting Integrin Allosteric Activation
'American Chemical Society (ACS)', 2018Co-Authors: Francesca Nardelli, Cristina Paissoni, Giacomo Quilici, Alessandro Gori, Catia Traversari, Barbara Valentinis, Angelina Sacchi, Angelo Corti, Flavio Curnis, Michela GhittiAbstract:The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that Cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-(N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with ( )alpha(v)beta(3), an integrin overexpressed in the tumor vasculature. Furthermore, we demonstrate that various Cyclopeptides containing the isoDGR sequence embedded in different molecular scaffolds do not induce ( )alpha(v)beta(3), allosteric activation and work as pure integrin antagonists. These results could be profitably exploited for the rational design of novel isoDGR-based ligands and tumor-targeting molecules with improved ( )alpha(v)beta(3)-binding properties and devoid of adverse integrin-activating effects
