%0 Journal Article
%T Amino Acid Derivatives as New Zinc Binding Groups for the Design of Selective Matrix Metalloproteinase Inhibitors
%A Mariateresa Giustiniano
%A Paolo Tortorella
%A Mariangela Agamennone
%A Antonella Di Pizio
%A Armando Rossello
%A Elisa Nuti
%A Isabel Gomez-Monterrey
%A Ettore Novellino
%A Pietro Campiglia
%A Ermelinda Vernieri
%A Marina Sala
%A Alessia Bertamino
%A Alfonso Carotenuto
%J Journal of Amino Acids
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/178381
%X A number of matrix metalloproteinases (MMPs) are important medicinal targets for conditions ranging from rheumatoid arthritis to cardiomyopathy, periodontal disease, liver cirrhosis, multiple sclerosis, and cancer invasion and metastasis, where they showed to have a dual role, inhibiting or promoting important processes involved in the pathology. MMPs contain a zinc (II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In an effort to devise new approaches to selective inhibitors, in this paper, we describe the synthesis and preliminary biological evaluation of amino acid derivatives as new zinc binding groups (ZBGs). The incorporation of selected metal-binding functions in more complex biphenyl sulfonamide moieties allowed the identification of one compound able to interact selectively with different MMP enzymatic isoforms. 1. Introduction Matrix metalloproteinases (MMPs) are 23-member zinc-dependent endopeptidases family involved in the extracellular matrix turnover [1]. Their aberrant regulation has been implicated in tumoral process, where they showed to have a dual role inhibiting or promoting cell growth and survival, angiogenesis and metastasis [2, 3] differentiation [4], and inflammation and immune surveillance [5]. Moreover, MMPs are overexpressed in a variety of tumor types, and their overexpression is associated with tumor aggressiveness and poor prognosis [6]. The specific alteration of the MMPs in malignant tissues and their participation in some of the major oncogenic mechanisms have both fuelled interest in the design and evaluation of MMP inhibitors (MMPIs) as anticancer agents [7, 8]. Generally, the MMPIs design involves peptide or peptidomimetic backbones containing a zinc-binding group (ZBG) able to interact with both the subpockets surrounding the active site ( and , , and ) and the zinc (II) ion present in the catalytic site, respectively [9, 10]. The greater part of MMPIs research has focused on developing the peptide or peptidomimetic containing a hydroxamic acid as chelating group. Although this design has produced potent inhibitors such as Batimastat [11, 12] and Marimastat [13] (Figure 1), none of these MMPIs has successfully completed clinical trials. Figure 1: Structures of Batimastat and Marimastat. The inability of hydroxamates to produce clinically viable compounds has been attributed to low oral availability, poor in vivo stability, and undesirable side effects associated with these compounds [14]. This has prompted the
%U http://www.hindawi.com/journals/jaa/2013/178381/