Abstract

Specific inhibition of the copper-containing peptidylglycine alpha-hydroxylating monooxygenase (PHM), which catalyzes the post-translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure-activity study of new compounds derived from a well-known PHM substrate analogue, the olefinic compound 4-phenyl-3-butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2d, for example, bears a meta-benzyloxy substituent, and exhibits better inhibition features (K(i) = 3.9 mu m, k(inact)/K(i) = 427 M(-1) s(-1)) than the parent PBA (K(i) = 19 mu m, k(inact)/K(i) = 82 M(-1) s(-1)). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features.

Autore Pugliese

• Saviano Michele

Tutti gli autori

• Langella E. ; Pierre S.; Ghattas W.; Giorgi M.; Reglier M.; Saviano M.; Esposito L.; Hardre R.

Titolo volume/Rivista

ChemMedChem

Anno di pubblicazione

2010

ISSN

1860-7179

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

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Numero di citazioni Scopus

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Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

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