Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors

Autoren

Valeria Troiano
Kety Scarbaci
Roberta Ettari
Nicola Micale
Carmen Cerchia
Andrea Pinto
Tanja Schirmeister
Ettore Novellino
Silvana Grasso
Antonio Lavecchia
Maria Zappalà

DOI

10.1016/j.ejmech.2014.06.017

ISSN

0223-5234

Zeitschrift

European Journal of Medicinal Chemistry

Sprache

en

Paginierung

1 - 14

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.ejmech.2014.06.017

Datum der Datenerfassung

2020

Titel

Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors

Ausgabe der Zeitschrift

83

Datenquelle: Crossref

Abstract

A new series of pseudopeptide boronate proteasome inhibitors (2-3) was developed, through optimization of our previously described analogs of bortezomib, bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment (1). The biological evaluation on human 20S proteasome displayed a promising inhibition profile, especially for compounds bearing a P2 ethylene fragment, which exhibited Ki values in the nanomolar range for the ChT-L activity (e.g. 2a, Ki = 0.057 μM) and considerable selectivity for proteasome over bovine pancreatic α-chymotrypsin. Docking experiments into the yeast 20S proteasome revealed that the ligands are accommodated predominantly into the ChT-L site and that they covalently bind to the active site threonine residue via boron atom. Within the cellular assays performed against a 60 cancer cell line panel, compounds 3e and 3f demonstrated also good antiproliferative activity and compound 3f emerged as promising lead compound for the development of anticancer agents targeting melanoma and non-small cell lung cancer.

Addresses

Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.

Autoren

Valeria Troiano
Kety Scarbaci
Roberta Ettari
Nicola Micale
Carmen Cerchia
Andrea Pinto
Tanja Schirmeister
Ettore Novellino
Silvana Grasso
Antonio Lavecchia
Maria Zappalà

DOI

10.1016/j.ejmech.2014.06.017

eISSN

1768-3254

Externe Identifier

PubMed Identifier: 24946214

Open access

false

ISSN

0223-5234

Zeitschrift

European journal of medicinal chemistry

Schlüsselwörter

Cell Line, Tumor
Animals
Cattle
Humans
Boronic Acids
Pyrazines
Proteasome Endopeptidase Complex
Endopeptidases
Caspases
Trypsin
Antineoplastic Agents
Cell Proliferation
Protein Conformation
Hydrolysis
Drug Design
Peptidomimetics
Proteolysis
Proteasome Inhibitors
Molecular Docking Simulation
Bortezomib

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

1 - 14

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

83

Datenquelle: Europe PubMed Central

Abstract

A new series of pseudopeptide boronate proteasome inhibitors (2-3) was developed, through optimization of our previously described analogs of bortezomib, bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment (1). The biological evaluation on human 20S proteasome displayed a promising inhibition profile, especially for compounds bearing a P2 ethylene fragment, which exhibited Ki values in the nanomolar range for the ChT-L activity (e.g. 2a, Ki = 0.057 μM) and considerable selectivity for proteasome over bovine pancreatic α-chymotrypsin. Docking experiments into the yeast 20S proteasome revealed that the ligands are accommodated predominantly into the ChT-L site and that they covalently bind to the active site threonine residue via boron atom. Within the cellular assays performed against a 60 cancer cell line panel, compounds 3e and 3f demonstrated also good antiproliferative activity and compound 3f emerged as promising lead compound for the development of anticancer agents targeting melanoma and non-small cell lung cancer.

Date of acceptance

2014

Autoren

Valeria Troiano
Kety Scarbaci
Roberta Ettari
Nicola Micale
Carmen Cerchia
Andrea Pinto
Tanja Schirmeister
Ettore Novellino
Silvana Grasso
Antonio Lavecchia
Maria Zappalà

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24946214

DOI

10.1016/j.ejmech.2014.06.017

eISSN

1768-3254

Zeitschrift

Eur J Med Chem

Schlüsselwörter

Docking studies
Peptidomimetic boronates
Proteasome inhibitors
Animals
Antineoplastic Agents
Boronic Acids
Bortezomib
Caspases
Cattle
Cell Line, Tumor
Cell Proliferation
Drug Design
Endopeptidases
Humans
Hydrolysis
Molecular Docking Simulation
Peptidomimetics
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Conformation
Proteolysis
Pyrazines
Trypsin

Sprache

eng

Country

France

Paginierung

1 - 14

PII

S0223-5234(14)00536-4

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

83

Datenquelle: PubMed

Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors

Werkzeuge