Novel Octreotide Dicarba-analogues with High Affinity and Different Selectivity for Somatostatin Receptors

Cianni, Alessandra Di; Carotenuto, Alfonso; Brancaccio, Diego; Novellino, Ettore; Reubi, Jean Claude; Beetschen, Karin; Papini, Anna Maria; Ginanneschi, Mauro

doi:10.1021/jm1005868

Cited by 35 publications

(33 citation statements)

References 45 publications

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“…This imposes challenges for examining the role of olefin geometry in the stability and biological activity of stapled peptides, which, to date, has not been thoroughly explored. 106,121−123 To this end, we employed catalysts 1 and 2 in Z -selective RCM for stapling α-helical peptides that encompass the vast majority of peptides used for biological studies.…”

Section: Resultsmentioning

confidence: 99%

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

2014

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Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclometalated ruthenium catalysts has led to new strategies for achieving such control with high fidelity and Z selectivity, but the scope and limitations of these catalysts on substrates bearing multiple functionalities, including peptides, remained unexplored. Herein, we report an assessment of various factors that contribute to both productive and nonproductive Z-selective metathesis on peptides. The influence of sterics, side-chain identity, and preorganization through peptide secondary structure are explored by homodimerization, cross metathesis, and ring-closing metathesis. Our results indicate that the amino acid side chain and identity of the olefin profoundly influence the activity of cyclometalated ruthenium catalysts in Z-selective metathesis. The criteria set forth for achieving high conversion and Z selectivity are highlighted by cross metathesis and ring-closing metathesis on diverse peptide substrates. The principles outlined in this report are important not only for expanding the scope of Z-selective olefin metathesis to peptides but also for applying stereoselective olefin metathesis in general synthetic endeavors.

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Section: Resultsmentioning

confidence: 99%

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

2014

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“…However, although our results strengthen the hypothesis of a specific ligand binding, they also reveal an IC 50 value of about 1–5 μM, which is low compared to peptide-based molecules that are used in clinical targeting approaches. Prominent examples are the somatostatin analogon octreotide and the αvβ3 integrin targeting RGD sequence, which show nanomolar binding affinities towards their targets [21,22]. Therefore, a major issue of further investigation is the enhancement of the ligand’s affinity.…”

Section: Resultsmentioning

confidence: 99%

Binding of the Phage Display Derived Peptide CaIX-P1 on Human Colorectal Carcinoma Cells Correlates with the Expression of Carbonic Anhydrase IX

Askoxylakis

Ehemann

Rana

et al. 2012

IJMS

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Phage display represents an attractive screening strategy for the identification of novel, specific binding ligands that could be used for tumor targeting. Recently, a new peptide (CaIX-P1) with affinity for human carbonic anhydrase IX (CAIX) was identified and evaluated. The aim of the present study is to characterize the properties of CaIX-P1 for targeting human colorectal carcinoma and investigate the correlation of peptide binding with the expression of carbonic anhydrase IX. Human colorectal carcinoma HCT116 and HT29 cells were investigated for CAIX expression using Western Blot analysis. Binding and competition studies of 125I-radiolabeled CaIX-P1 were performed on HCT116 cells in vitro. FACS analysis and fluorescence microscopy studies were carried out after cell incubation with fluorescein-labeled CaIX-P1 and rhodamine-labeled anti-human CAIX-mAb. Our studies revealed an enhanced in vitro expression of carbonic anhydrase IX in HCT116 and HT29 cells with increasing cell density. Binding of 125I-labeled-CaIX-P1 on HCT116 cells increased with increasing cell density and correlated to the CAIX expression. FACS analysis demonstrated a correlation of cell labeling between FITC-CaIX-P1 and rhodamine-labeled anti-CAIX-mAb in both HCT116 and HT29 cells. The results of our study indicate that the phage display identified peptide CaIX-P1 might be an attractive candidate for the development of a ligand targeting CAIX in colorectal cancer.

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“…Clinical usefulness of SST is limited by its very short half‐life. Several synthetic SST analogs, including octreotide (OCT), lanreotide, and vapreotide, have improved metabolic stability and increased affinity to SSTRs …”

Section: Introductionmentioning

confidence: 99%

Somatostatin Receptor–Mediated Specific Delivery of Paclitaxel Prodrugs for Efficient Cancer Therapy

Huo

Zhu

et al. 2015

Journal of Pharmaceutical Sciences

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Novel Octreotide Dicarba-analogues with High Affinity and Different Selectivity for Somatostatin Receptors

Cited by 35 publications

References 45 publications

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Z-Selective Olefin Metathesis on Peptides: Investigation of Side-Chain Influence, Preorganization, and Guidelines in Substrate Selection

Binding of the Phage Display Derived Peptide CaIX-P1 on Human Colorectal Carcinoma Cells Correlates with the Expression of Carbonic Anhydrase IX

Somatostatin Receptor–Mediated Specific Delivery of Paclitaxel Prodrugs for Efficient Cancer Therapy

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