Development of peptidomimetic boronates as proteasome inhibitors

Autoren

Nicola Micale
Roberta Ettari
Antonio Lavecchia
Carmen Di Giovanni
Kety Scarbaci
Valeria Troiano
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Maria Zappalà

DOI

10.1016/j.ejmech.2013.03.032

ISSN

0223-5234

Zeitschrift

European Journal of Medicinal Chemistry

Sprache

en

Paginierung

23 - 34

Datum der Veröffentlichung

2013

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.ejmech.2013.03.032

Datum der Datenerfassung

2018

Titel

Development of peptidomimetic boronates as proteasome inhibitors

Ausgabe der Zeitschrift

64

Data source: Crossref

Abstract

Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (β5), trypsin-like (β2) and caspase-like (β1). Most important for the development of effective antitumor agents is the inhibition of the β5 subunits. In this context, the dipeptide boronate bortezomib (Velcade(®)) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with Ki values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic α-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors.

Addresses

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

Autoren

Nicola Micale
Roberta Ettari
Antonio Lavecchia
Carmen Di Giovanni
Kety Scarbaci
Valeria Troiano
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Maria Zappalà

DOI

10.1016/j.ejmech.2013.03.032

eISSN

1768-3254

Externe Identifier

PubMed Identifier: 23639651

Funding acknowledgements

Deutsche Forschungsgemeinschaft:
Ministero dell'Istruzione, dell'Università e della Ricerca Scientifica e Tecnologica: MIUR-PRIN2010-2011

Open access

false

ISSN

0223-5234

Zeitschrift

European journal of medicinal chemistry

Schlüsselwörter

Humans
Boron Compounds
Proteasome Endopeptidase Complex
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
Models, Molecular
Peptidomimetics
Proteasome Inhibitors

Sprache

eng

Medium

Print-Electronic

Online publication date

2013

Paginierung

23 - 34

Datum der Veröffentlichung

2013

Status

Published

Datum der Datenerfassung

2013

Titel

Development of peptidomimetic boronates as proteasome inhibitors.

Sub types

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

Ausgabe der Zeitschrift

64

Data source: Europe PubMed Central

Abstract

Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (β5), trypsin-like (β2) and caspase-like (β1). Most important for the development of effective antitumor agents is the inhibition of the β5 subunits. In this context, the dipeptide boronate bortezomib (Velcade(®)) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with Ki values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic α-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors.

Date of acceptance

2013

Autoren

Nicola Micale
Roberta Ettari
Antonio Lavecchia
Carmen Di Giovanni
Kety Scarbaci
Valeria Troiano
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Maria Zappalà

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/23639651

DOI

10.1016/j.ejmech.2013.03.032

eISSN

1768-3254

Zeitschrift

Eur J Med Chem

Schlüsselwörter

Boron Compounds
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Peptidomimetics
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Structure-Activity Relationship

Sprache

eng

Country

France

Paginierung

23 - 34

PII

S0223-5234(13)00192-X

Datum der Veröffentlichung

2013

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2013

Titel

Development of peptidomimetic boronates as proteasome inhibitors.

Sub types

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

Ausgabe der Zeitschrift

64

Data source: PubMed

Development of peptidomimetic boronates as proteasome inhibitors

Tools