A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors

Tulsi, Naresh S.; Downey, A. Michael; Cairo, Christopher W.

doi:10.1016/j.bmc.2010.09.040

Cited by 23 publications

(15 citation statements)

References 44 publications

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“…These results indicate that tripeptide 11 was more potent than BrPmp alone, suggesting additional interactions of the peptide side chains to improve enzyme binding. 106 …”

Section: Covalent Ptp Inhibitorsmentioning

confidence: 99%

Covalent inhibition of protein tyrosine phosphatases

Ruddraraju

Zhang

2017

Mol. BioSyst.

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Protein tyrosine phosphatases (PTPs) are a large family of 107 signaling enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in a target protein. The phosphorylation status of tyrosine residues on proteins serve as a ubiquitous mechanism for cellular signal transduction. Aberrant function of PTPs can lead to many human diseases, such as diabetes, obesity, cancer, and autoimmune diseases. As the number of disease relevant PTPs increases, there is urgency in developing highly potent inhibitors that are selective towards specific PTPs. Most current efforts have been devoted to the development of active site-directed and reversible inhibitors for PTPs. This review summarizes recent progress made in the field of covalent inhibitors to target PTPs. Here, we discuss the in vivo and in vitro inactivation of various PTPs by small molecule-containing electrophiles, such as Michael acceptors, α-halo ketones, epoxides, and isothiocyanates, etc. as well as oxidizing agents. We also suggest potential strategies to transform these electrophiles into isozyme selective covalent PTP inhibitors.

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“…These results indicate that tripeptide 11 was more potent than BrPmp alone, suggesting additional interactions of the peptide side chains to improve enzyme binding. 106 …”

Section: Covalent Ptp Inhibitorsmentioning

confidence: 99%

Covalent inhibition of protein tyrosine phosphatases

Ruddraraju

Zhang

2017

Mol. BioSyst.

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“…39 These studies were the rst to demonstrate that a-bromobenzylphosphonates could be used successfully for selective, irreversible inhibition of PTPs as an enzyme class. 40 These results strongly suggest that an appropriate BrPmp peptide sequence could be used to target an individual PTP enzyme with high potency. 46 It is worth noting that these studies also raise the concern that, while extremely active, the a-BBP functional group alone does not provide specicity among different PTPs.…”

Section: Benzylic A-bromophosphonatesmentioning

confidence: 86%

“…39 Importantly, when probe 5 was introduced into a mixture PTPs (YopH, PTP1b, HePTP, SHP2, FAP-1, PTPa, DEP-1, VHR, Cdc14 and PRL-3) at 1 mM concentration, covalent adducts were formed with all enzymes. 40 Tulsi et al conrmed that 6 was indeed a covalent inhibitor of CD45 using a Kitz-Wilson analysis with a similar rate of inactivation to that of tripeptide 11. 39 These studies were the rst to demonstrate that a-bromobenzylphosphonates could be used successfully for selective, irreversible inhibition of PTPs as an enzyme class.…”

Section: Benzylic A-bromophosphonatesmentioning

confidence: 99%

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Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Downey

Cairo

2014

Med. Chem. Commun.

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Substrate phosphorylation is a key modulator of signal transduction. Abnormal phosphorylation in vivo is implicated in many diseases including cancer, diabetes, and Alzheimer's disease. Inhibitors of phosphaterecognizing proteins have potential as medicinal agents as well as tools to study phosphorylation pathways. A well-known and common inhibition strategy is to synthetically replace the labile phosphate moiety with a non-hydrolyzable phosphonate. Fully saturated, a-fluoro and a,a-difluorophosphonates are often effective phosphate bioisosteres and have been well studied. More recently a-brominated phosphonates have begun to emerge as inhibitors of phosphate recognizing enzymes, some of which operate by irreversible mechanisms. Herein we discuss the synthetic approaches to aliphatic and benzylic a-bromophosphonates and their biological activities.Scheme 5 The synthesis of an aliphatic a-bromophosphonate derivative. 52 Scheme 6 An improved synthetic strategy to alkyl abromophosphonates. 53This journal is

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“…One synthetic route to α‐hydroxyphosphonic acids involves the hydrolysis of α‐hydroxyphosphonates in the presence of hydrochloric acid used in an excess . Another widely applied method is the fission of the C–O bond of the ester function of α‐hydroxyphosphonates using trimethylsilyl bromide, followed by hydrolysis . An oxidative method is also known, starting from α‐hydroxyalkyl‐ H ‐phosphinic acids, employing I 2 /DMSO as the oxidizing system .…”

Section: Introductionmentioning

confidence: 99%

Green synthesis and cytotoxic activity of dibenzyl α‐hydroxyphosphonates and α‐hydroxyphosphonic acids

Rádai

Szeles

Kiss

et al. 2018

Heteroatom Chemistry

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A series of dibenzyl α‐hydroxyphosphonates and the corresponding α‐hydroxyphosphonic acids, mostly new compounds, have been synthesized. The dibenzyl α‐hydroxyphosphonates have been obtained in the Pudovik reaction of substituted benzaldehydes and dibenzyl phosphite in the presence of triethylamine as the catalyst. The amount of the solvent was minimized during the reaction, and the workup involved crystallization from the reaction mixture. A new protocol was developed to transform the dibenzyl 1‐hydroxyphosphonates to the corresponding phosphonic acids by catalytic hydrogenation. The derivatives prepared were screened as potential cytotoxic agents against Mes‐Sa human uterine sarcoma cell line.

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A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors

Cited by 23 publications

References 44 publications

Covalent inhibition of protein tyrosine phosphatases

Covalent inhibition of protein tyrosine phosphatases

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Green synthesis and cytotoxic activity of dibenzyl α‐hydroxyphosphonates and α‐hydroxyphosphonic acids

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