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Furlan A.,Aix - Marseille University | Roux B.,Aix - Marseille University | Lamballe F.,Aix - Marseille University | Conti F.,Aix - Marseille University | And 10 more authors.
PLoS ONE | Year: 2012

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation. © 2012 Furlan et al. Source


Zagami M.,University of Milan | Binda M.,University of Milan | Piccolo O.,Studio di Consulenza Scientifica | Straniero V.,University of Milan | And 2 more authors.
Tetrahedron Letters | Year: 2012

(S)-(+)-3-Aminomethyl-5-methylhexanoic acid (pregabalin) was converted in one-pot to (S)-(-)-3-cyano-5-methylhexanoic acid (pregabalin nitrile) by N-dichlorination and double dehydrochlorination. The (S) β-cyanoacid was racemized under mild conditions by treatment with a base. This very simple and efficient procedure, applied to (R)-(-)-3-aminomethyl-5-methylhexanoic acid, would enable the recycling of the undesired enantiomer of pregabalin, an anticonvulsant drug manufactured by the synthesis of rac-3-aminomethyl-5- methylhexanoic acid and subsequent classical resolution. © 2012 Elsevier Ltd. All rights reserved. Source


Pallavicini M.,University of Milan | Bolchi C.,University of Milan | Fumagalli L.,University of Milan | Piccolo O.,Studio di Consulenza Scientifica | Valoti E.,University of Milan
Tetrahedron Asymmetry | Year: 2011

N-Chlorination by sodium dichloroisocyanurate and dehydrochlorination by TEA, followed by hydrogenation, allowed (1R,6S)-8-benzyl-7,9-dioxo-2,8- diazabicyclo[4.3.0]nonane to be quantitatively racemised and the resulting trans-free cis racemate to be recycled into the resolution process to yield (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, a key intermediate of moxifloxacin. © 2011 Elsevier Ltd. All rights reserved. Source


Furlan A.,Aix - Marseille University | Colombo F.,University of Milan | Kover A.,University of Barcelona | Issaly N.,Aix - Marseille University | And 15 more authors.
European Journal of Medicinal Chemistry | Year: 2012

The Met receptor tyrosine kinase is a promising target in anticancer therapies for its role during tumor evolution and resistance to treatment. It is characterized by an unusual structural plasticity as its active site accepts different inhibitor binding modes. Such feature can be exploited to identify distinct agents targeting tumor dependence and/or resistance by oncogenic Met. Here we report the identification of bioactive agents, featuring a new 4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl moiety, targeting cancer cells dependent on oncogenic Met. One of these compounds (7c; Triflorcas) impairs survival, anchorage-independent growth, and in vivo tumorigenesis, without showing side effects. Our medicinal chemistry strategy was based on an in-house Met-focused library of aminoacid-amide derivatives enriched through structure-based computer modeling, taking into account the Met multiple-binding-mode feature. Altogether, our findings show how a rational structure-based drug design approach coupled to cell-based drug evaluation strategies can be applied in medicinal chemistry to identify new agents targeting a given oncogenic-dependency setting. © 2011 Elsevier Masson SAS. All rights reserved. Source


Pallavicini M.,University of Milan | Bolchi C.,University of Milan | Fumagalli L.,University of Milan | Piccolo O.,Studio di Consulenza Scientifica | Valoti E.,University of Milan
Tetrahedron Letters | Year: 2010

N-monochlorination of N-unprotected α-amino esters and α-amino-β-diesters was efficiently and very simply effected by using inexpensive effervescent sodium dichloroisocyanurate tablets for water disinfection in a biphasic organic solvent-water system. Subsequent dehydrochlorination provided α,β-didehydroaminoacid esters, whose hydrogenation would allow the starting compounds to be easily racemized. © 2010 Elsevier Ltd. All rights reserved. Source

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