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Manzoni L.,CNR Institute of Molecular Science and Technologies | Belvisi L.,University of Milan | Bianchi A.,CISI Scrl | Conti A.,Fondazione IRCCS Instituto Nazionale Dei Tumori | And 12 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Novel pro-apoptotic, homo- and heterodimeric Smac mimetics/IAPs inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold were prepared from monomeric structures connected through a head-head (8), tail-tail (9) or head-tail (10) linker. The selection of appropriate decorating functions for the scaffolds, and of rigid and flexible linkers connecting them, is described. The synthesis, purification and analytical characterization of each prepared dimer 8-10 is thoroughly described. © 2012 Elsevier Ltd. All rights reserved.


Arosio D.,CNR Institute of Molecular Science and Technologies | Manzoni L.,CNR Institute of Molecular Science and Technologies | Araldi E.M.V.,University of Milan | Scolastico C.,CISI Scrl
Bioconjugate Chemistry | Year: 2011

Integrin αvβ3 is an adhesion molecule involved in physiological and pathological angiogenesis as well as tumor invasion and metastasis. Therefore, it is considered an important target for molecular imaging and delivery of therapeutics for cancer, and there is a strong interest in developing novel agents interacting with this protein. Nevertheless, the interaction of individual ligands is often still weak for efficient tumor targeting, and many research groups have synthesized multivalent displays in order to overcome this problem. Gold nanoparticles can be considered a smart platform for polyvalent presentation on account of their globular shape, tunable size, facile surface chemistry, and biocompatibility. Moreover, their unique physical properties render gold nanoparticles ideal candidates for tumor diagnosis and therapy. Here, we report the synthesis and characterization of gold nanoparticles functionalized with cRGD integrin ligand and their employment for targeting human cancer cells expressing αvβ3 integrin. © 2011 American Chemical Society.


Lecis D.,Fondazione IRCCS Instituto Nazionale Dei Tumori | Mastrangelo E.,CNR Institute of Biophysics | Belvisi L.,University of Milan | Bolognesi M.,CNR Institute of Biophysics | And 17 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents. © 2012 Elsevier Ltd. All rights reserved.


Patent
University of Milan, Fondazione Irccs Instituto Nazionale Dei Tumori, Cisi Scrl and Fondazione Cariplo | Date: 2016-09-28

The present invention relates to conformationally constrained homo- and heterodimeric mimetics of Smac with function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs), the invention also relates to the use of these compounds in therapy, wherein the induction of apoptotic cell death is beneficial, especially in the treatment of cancer, alone or in combination with other active ingredients.


Patent
University of Milan, Fondazione Cariplo, Cisi Scrl and Fondazione Irccs Instituto Nazionale Dei Tumori | Date: 2012-02-20

The present invention relates to conformationally constrained homo- and heterodimeric mimetics of Smac with function as inhibitors of Inhibitor of Apoptosis Proteins (IAPs), the invention also relates to the use of these compounds in therapy, wherein the induction of apoptotic cell death is beneficial, especially in the treatment of cancer, alone or in combination with other active ingredients.


Thanyarat U.,Chulalongkorn University | Thanyada R.,Chulalongkorn University | Vladimir F.,Comenius University | Vladimir F.,International Center for Applied Research and Sustainable Technology | And 6 more authors.
Current Pharmaceutical Design | Year: 2014

The outbreak of avian influenza A (H5N1) virus has raised a global concern for both the animal as well as human health. Besides vaccination, that may not achieve full protection in certain groups of patients, inhibiting neuraminidase or the transmembrane protein M2 represents the main measure of controlling the disease. Due to alarming emergence of influenza virus strains resistant to the currently available drugs, development of new neuraminidase N1 inhibitors is of utmost importance. The present paper provides an overview of the recent advances in the design of new antiviral drugs against avian influenza. It also reports findings in binding free energy calculations for nine neuraminidase N1 inhibitors (oseltamivir, zanamivir, and peramivir -carboxylate, -phosphonate, and -sulfonate) using the Linear Interaction Energy method. Molecular dynamics simulations of these inhibitors were performed in a free and two bound states - the so called open and closed conformations of neuraminidase N1. Obtained results successfully reproduce the experimental binding affinities of the already known neuraminidase N1 inhibitors, i.e. peramivir being a stronger binder than zanamivir that is in turn stronger binder than oseltamivir, or phosphonate inhibitors being stronger binders than their carboxylate analogues. In addition, the newly proposed sulfonate inhibitors are predicted to be the strongest binders - a fact to be confirmed by their chemical synthesis and a subsequent test of their biological activity. Finally, contributions of individual inhibitor moieties to the overall binding affinity are explicitly evaluated to assist further drug development towards inhibition of the H5N1 avian influenza A virus. © 2014 Bentham Science Publishers.


Bianchi A.,CISI Scrl | Ugazzi M.,University of Milan | Ferrante L.,CISI Scrl | Lecis D.,Fondazione IRCCS Instituto Nazionale Tumori | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A set of phenyl-substituted Smac mimetics/IAP inhibitor analogues of lead compound 2a was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compounds 2b-r were prepared and characterized in vitro, using cell-free and cellular assays. Among them, the p-CF 3 substituted analogue 2m showed the best permeability through cell membranes, and was selected for further in vitro and in vivo studies due to its strong, sub-micromolar cellular potency. © 2011 Elsevier Ltd. All rights reserved.

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