A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probesThe authors declare no competing interest.Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds 9 and 10, in vitro LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI: 10.1039/c5md00462d
Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologicall...
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16.03.2016
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Abstract | Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes.
Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. |
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AbstractList | Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes.
Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. |
Author | Maga, Giovanni Crespan, Emmanuele Radi, Marco Costantino, Gabriele Castagnolo, Daniele Giagnorio, Federica Armijos-Rivera, Jorge I Scalacci, Nicolò Kissova, Miroslava Tassini, Sabrina |
AuthorAffiliation | Università degli Studi di Parma King's College London Northumbria University Newcastle Department of Applied Sciences P4T Group, Dipartimento di Farmacia Institute of Pharmaceutical Science Istituto di Genetica Molecolare |
AuthorAffiliation_xml | – name: P4T Group, Dipartimento di Farmacia – name: Institute of Pharmaceutical Science – name: Northumbria University Newcastle – name: Università degli Studi di Parma – name: King's College London – name: Department of Applied Sciences – name: Istituto di Genetica Molecolare |
Author_xml | – sequence: 1 givenname: Sabrina surname: Tassini fullname: Tassini, Sabrina – sequence: 2 givenname: Daniele surname: Castagnolo fullname: Castagnolo, Daniele – sequence: 3 givenname: Nicolò surname: Scalacci fullname: Scalacci, Nicolò – sequence: 4 givenname: Miroslava surname: Kissova fullname: Kissova, Miroslava – sequence: 5 givenname: Jorge I surname: Armijos-Rivera fullname: Armijos-Rivera, Jorge I – sequence: 6 givenname: Federica surname: Giagnorio fullname: Giagnorio, Federica – sequence: 7 givenname: Giovanni surname: Maga fullname: Maga, Giovanni – sequence: 8 givenname: Gabriele surname: Costantino fullname: Costantino, Gabriele – sequence: 9 givenname: Emmanuele surname: Crespan fullname: Crespan, Emmanuele – sequence: 10 givenname: Marco surname: Radi fullname: Radi, Marco |
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Notes | 10.1039/c5md00462d and in vitro 9 , The authors declare no competing interest. Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI 10 |
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Title | A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probesThe authors declare no competing interest.Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds 9 and 10, in vitro LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI: 10.1039/c5md00462d |
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