Recent advances in synthetic and medicinal chemistry of phosphotyrosine and phosphonate-based phosphotyrosine analogues

Makukhin, Nikolai; Ciulli, Alessio

doi:10.1039/d0md00272k

Cited by 23 publications

(23 citation statements)

References 93 publications

(181 reference statements)

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“…Therefore, to evaluate whether the Tyr residue affects the binding of ICAM-1 to SRC, we created a phosphomimetic mutant in which the Tyr residue was either unphosphorylated or remains active without the need to be phosphorylated (Fig. 3E ) [ 26 ]. Co-IP and PLA results revealed that when the Tyr residue was substituted with alanine, it did not bind to SRC, whereas when it was substituted with aspartic acid, the binding significantly increased (Fig.…”

Section: Resultsmentioning

confidence: 99%

ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer

et al. 2022

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Colorectal cancer (CRC) has a 5-year survival rate of <10%, as it can metastasize to the lungs and liver. Anticancer drugs and targeted therapies used to treat metastatic colorectal cancer have insufficient therapeutic efficacy and are associated with complications. Therefore, research to develop new targeted therapeutics is necessary. Here, we present a novel discovery that intracellular adhesion molecule-1 (ICAM-1) is a potential therapeutic target to enhance therapeutic effectiveness for CRC. ICAM-1 is an important regulator of cell–cell interactions and recent studies have shown that it promotes malignancy in several carcinomas. However, little is known about its effect on CRC. Therefore, we conducted a study to define the mechanism by which ICAM-1 acts. ICAM-1 is phosphorylated by tyrosine-protein kinase Met (c-MET), and phosphorylated ICAM-1 can interact with SRC to increase SRC activity. Consequently, ICAM-1 may further accelerate SRC signaling, promoting the malignant potential of cancer. In addition, treatment with antibodies targeting ICAM-1 showed excellent therapeutic effects in reducing metastasis and angiogenesis. These findings suggest for the first time that ICAM-1 is an important adapter protein capable of mediating the c-MET-SRC signaling axis. Therefore, ICAM-1 can be used as a novel therapeutic target and a metastatic marker for CRC.

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Section: Resultsmentioning

confidence: 99%

ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer

et al. 2022

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“…For a profound understanding of protein tyrosine phosphorylation chemical tools are required to bind, inhibit or manipulate phosphotyrosine binding sites without being prone to enzymatic cleavage or dephosphorylation. To date the most potent “gold standard” phosphotyrosine mimetic is 4‐phosphono‐difluoromethyl‐phenylalanine (PDFM‐Phe) 1 and numerous studies have demonstrated highly potent and selective inhibitors with this structure integrated in peptide sequences (Scheme 1A) [5, 6] . Phosphonic acids, however, are strong acids and form highly polar di‐anions resulting in low membrane permeability and thus inactivity in cells [7]…”

Section: Methodsmentioning

confidence: 99%

“…To date the most potent "gold standard" phosphotyrosine mimetic is 4-phosphono-difluoromethyl-phenylalanine (PDFM-Phe) 1 and numerous studies have demonstrated highly potent and selective inhibitors with this structure integrated in peptide sequences (Scheme 1A). [5,6] Phosphonic acids, however, are strong acids and form highly polar di-anions resulting in low membrane permeability and thus inactivity in cells. [7] Considering that phosphate binding sites are coated with a positively charged surface resulting from cationic arginine residues and from H-bond donors, [8] we hypothesized that fragments containing fluorine atoms with negative partial charge might act as H-bond acceptors and thus might be useful as phosphate mimetics.…”

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confidence: 99%

Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions

et al. 2022

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Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF 5 -amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine-specific interactions were studied by NMR and IR spectroscopy, X-ray diffraction, and in bioactivity assays. The mono-anionic PF 5 motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein-binding sites, exploiting charge and HÀ F-bonding interactions. The novel motifs bind 25-to 30-fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations.

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“…Für ein fundiertes Verständnis der Proteintyrosin‐Phosphorylierung sind daher chemische Werkzeuge von Nöten, die an die Proteintyrosin‐Bindungstasche binden und diese inhibieren oder manipulieren, ohne dabei enzymatisch gespalten oder dephosphoryliert zu werden. Der derzeitige “Goldstandard” für Mimetika ist 4‐Phosphono‐Difluormethylphenylalanin (PDFM‐Phe) 1 und zahlreiche Studien zeigten hochpotente und selektive Inhibitoren, in denen dieser Baustein in eine Peptidstruktur eingebaut wurde (Schema 1A) [5, 6] . Phosphonsäuren sind jedoch starke Säuren und liegen als hochpolare Dianionen vor, was geringe Membranpermeabilität und daher Inaktivität in Zellen zur Folge hat [7]…”

Section: Methodsunclassified

Pentafluorphosphato‐Phenylalanine: Amphiphile Phosphotyrosinmimetika mit Fluor‐spezifischen Proteinwechselwirkungen

et al. 2022

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Phosphotyrosinreste sind essenzielle funktionale Schalter in Gesundheit und Krankheit. Daher sind Phosphotyrosin‐Biomimetika entscheidend für die Entwicklung von chemischen Werkzeugen und Wirkstoffmolekülen. Hier beschreiben wir die Entdeckung und Untersuchung von Pentafluorphosphato‐Aminosäuren als neuartige Phosphotyrosinmimetika. Ein mildes Pentafluorierungsprotokoll wurde entwickelt, zwei PF5‐Aminosäuren hergestellt und für die Peptidsynthese verwendet. Ihre Strukturen, Reaktivitäten und fluorspezifischen Wechselwirkungen wurden mittels NMR‐ und IR‐Spektroskopie, Röntgenstreuung und biologischen Assays untersucht. Das monoanionische PF5‐Motiv weist einen amphiphilen Charakter auf und bindet an hydrophobe Oberflächen, Wassermoleküle und Proteinbindungstaschen mittels Ladungs‐ und H−F‐Brückenwechselwirkungen. Die neuen Motive binden 25‐ bis 30‐fach stärker an die Phosphotyrosinbindungsstelle der Proteintyrosin‐Phosphatase PTP1B als das derzeit beste Biomimetikum, wie durch computergestützte Methoden wie Moleküldynamiksimulationen rationalisiert werden konnte.

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Recent advances in synthetic and medicinal chemistry of phosphotyrosine and phosphonate-based phosphotyrosine analogues

Abstract: This review summarizes advances over the last decade in the design of phosphotyrosine and its phosphonate-based derivatives, focusing on their synthesis and medicinal chemistry applications.

Cited by 23 publications

References 93 publications

ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer

ICAM-1 promotes cancer progression by regulating SRC activity as an adapter protein in colorectal cancer

Pentafluorophosphato‐Phenylalanines: Amphiphilic Phosphotyrosine Mimetics Displaying Fluorine‐Specific Protein Interactions

Pentafluorphosphato‐Phenylalanine: Amphiphile Phosphotyrosinmimetika mit Fluor‐spezifischen Proteinwechselwirkungen

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