Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13.

Autor: Agamennone M; Dipartimento di Farmacia, Università 'G. d'Annunzio', Chieti, Via dei Vestini 31, 66013, Chieti, Italy. m.agamennone@unich.it., Belov DS; EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy.; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia., Laghezza A; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi 'Aldo Moro' di Bari, Via Orabona 4, 70126, Bari, Italy., Ivanov VN; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia., Novoselov AM; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia., Andreev IA; EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy.; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia., Ratmanova NK; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia., Altieri A; EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy., Tortorella P; Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi 'Aldo Moro' di Bari, Via Orabona 4, 70126, Bari, Italy., Kurkin AV; Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia. kurkin@direction.chem.msu.ru.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2016 Sep 06; Vol. 11 (17), pp. 1892-8. Date of Electronic Publication: 2016 Jul 15.
DOI: 10.1002/cmdc.201600266
Abstrakt: Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.
(© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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