<i>N-O-</i>Isopropyl Sulfonamido-Based Hydroxamates: Design, Synthesis and Biological Evaluation of Selective Matrix Metalloproteinase-13 Inhibitors as Potential Therapeutic Agents for Osteoarthritis

Nuti, Elisa; Casalini, Francesca; Avramova, Stanislava I.; Santamaria, Salvatore; Cercignani, Giovanni; Marinelli, Luciana; Pietra, Valeria La; Novellino, Ettore; Orlandini, Elisabetta; Nencetti, Susanna; Tuccinardi, Tiziano; Martinelli, Adriano; Lim, Ngee Han; Visse, Robert; Nagase, Hideaki; Rossello, Armando

doi:10.1021/jm900261f

Cited by 60 publications

(39 citation statements)

References 64 publications

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“…Compound ML25 was synthesised as reported in Scheme 4. Carboxylic acid 12 was prepared by acid hydrolysis of the previously described tert-butyl ester 11 [26]. The corresponding hydroxamic acid ML25 was obtained by condensation of 12 with O-(tertbutyldimethylsilyl)hydroxylamine followed by acid cleavage with TFA.…”

Section: Scheme 1 Synthesis Of Compound En204mentioning

confidence: 99%

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Sjøli

Nuti

Camodeca

et al. 2016

European Journal of Medicinal Chemistry

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Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from grampositive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S2 ' subpocket by an aromatic group is favourable for strong interactions with pseudolysin.

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Section: Scheme 1 Synthesis Of Compound En204mentioning

confidence: 99%

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Sjøli

Nuti

Camodeca

et al. 2016

European Journal of Medicinal Chemistry

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“…FABdil stands for FAB solution diluted 1:4 with water. Inhibitors 1-4 [18] and 5 [19] were prepared as previously described. Epoxy-activated Sepharose 6B and EAH Sepharose 4B were purchased from GE Healthcare and prepared for coupling according to manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…4) was carried out both on free and EPSi-MMP-8 ( Table 2). The MMP-8 inhibitory activity of those compounds had been previously determined by plate reader fluorometric assay [18,19]. The ranking of the inhibitors potency observed with solubilized and immobilized enzyme resulted the same (5 > 4 > 3-2 > 1), showing that the interactions with the catalytic domain of MMP-8 were not affected by the immobilization.…”

Section: Inhibition and Affinity Studymentioning

confidence: 99%

Immobilization of matrix metalloproteinase 8 (MMP-8) for online drug screening

Mazzini

Nuti

Petri

et al. 2011

Journal of Chromatography B

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“…MMP-13 is the main collagenase responsible for cartilage degradation, and it represents a potential target for the development of new DMOADs (disease-modifying OA drugs) [72].…”

Section: Pathogenesismentioning

confidence: 99%

Chondropenia: current concept review

et al. 2015

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The term "chondropenia" indicates the early stage of degenerative cartilage disease, and it has been identified by carefully monitoring early-stage osteoarthritis (OA). Not only is it the loss of articular cartilage volume, but it is also a rearrangement of biomechanical, ultrastructural, biochemical and molecular properties typical of healthy cartilage tissue. Diagnosing OA at an early stage or an advanced stage is valuable in terms of clinical and therapeutic outcome. In fact degenerative phenomena are supported by a complex biochemical cascade which unbalances the extracellular matrix homeostasis, closely regulated by chondrocytes. In the first stage an intense inflammatory reaction is triggered: pro-catabolic cytokines such as IL-1β and TNF-α triggering matrix metalloproteases and aggrecanase (ADAMT-4 and 5), responsible for the early loss of ultrastructural components, such as type II collagen and aggrecan. In addition nitric oxide and reactive oxygen species modulate the physiopathology of the condral matrix inducing apoptosis of chondrocytes through a mitochondria-dependent pathway. In addition, "Lonely Death": chondrocytes, are confined within a dense, avascular extracellular matrix capsule, and can trigger a genetically induced apoptosis and necrosis. The degenerative process starts from a central point and then spreads in a centrifugal manner in depth and in adjacent areas, eventually covering the whole joint; chondropenia represents a journey from the first clinically detectable time-point until it can be characterized as frank osteoarthritis. Currently, there are no instruments sensitive enough which allow a timely diagnosis of chondropenia. Innovative magnetic resonance imaging techniques, such as T2 mapping, can be effective and a sensitive diagnostic instrument for quantifying cartilage volume and proteoglycan content. However, avant-garde biophysical techniques, such as mechanical indenters, ultrasound and biochemical markers (uCTX-II), are rational and scientific tools applicable to the clinical and therapeutic management of early degenerative cartilage disease. The objective of this review on chondropenia is to present a state of the art and innovative concepts.

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N-O-Isopropyl Sulfonamido-Based Hydroxamates: Design, Synthesis and Biological Evaluation of Selective Matrix Metalloproteinase-13 Inhibitors as Potential Therapeutic Agents for Osteoarthritis

Cited by 60 publications

References 64 publications

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors

Immobilization of matrix metalloproteinase 8 (MMP-8) for online drug screening

Chondropenia: current concept review

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