Solid-phase synthesis of α-substituted 3-bisarylthio N-Hydroxy propionamides as Specific MMP Inhibitors

Chollet, Anne‐Marie; Diguarher, Thierry Le; Kucharczyk, Nathalie; Loynel, Armelle; Bertrand, Marc; Tucker, Gordon C.; Guilbaud, Nicolas; Burbridge, Mike F.; Pastoureau, Philippe; Fradin, Armel; Sabatini, Massimo; Fauchère, Jean‐Luc; Casara, Patrick

doi:10.1016/s0968-0896(01)00311-x

Cited by 32 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GM6001 (Chemicon, Temecula, CA) is another broad spectrum hydroxamate MMPI with reported IC 50 values as follows: MMP-1, 0.4 nM; MMP-2, 0.5 nM; MMP-3, 27 nM; MMP-8, 0.1 nM; and MMP-9, 0.2 nM. We also used two other hydroxamate inhibitors, the compound 6A (Hanessian et al, 2001), and the S34237 (Chollet et al, 2002), chemically modified at the P 1 , P 1 0, and P 2 0 sites to enhance their specificity for MMP-9 and MMP-2, respectively. Enzymatic assays with purified proteinases using the MMP-9 inhibitor (MMP-9I) yielded the following IC 50 values: MMP-1, 104 nM; MMP-2, 0.7 nM; MMP-3, 0.7 nM; MMP-9, 0.0025 nM; and MMP-13, 12 nM.…”

Section: Proteinase Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Ogier

Bernard

Chollet

et al. 2006

Glia

Self Cite

110

View full text Add to dashboard Cite

Matrix Metalloproteinases (MMPs) play a role in migration of many cell types outside the central nervous system (CNS). Among neural cells, astrocytes are one of the main sources of MMPs in physiological and postlesional conditions. However, no data are available on the possible role of MMPs in astrocyte motility. Using an in vitro model of 2D migration and broad spectrum and selective MMP inhibitors, the authors demonstrated that MMP-2, but not MMP-9, is a key enzyme for astrocyte migration. In support of these data, the authors found constitutive expression of MMP-2 in astrocytes, while MMP-9 was nearly undetectable by gel zymography and immunocytochemical methods. The inhibition of migration by MMP inhibitors correlated with changes in cell morphology and in the organization of the actin cytoskeleton. In parallel, the characteristic focalized distribution of MMP-2 at the migration front observed in control cells became more diffuse and internalized by treatments that inhibited migration. The disruption of actin by cytochalasin D caused the partial recruitment of MMP-2 and gelatinolytic activity into actin aggregates, indicating a connection between the proteinase and the actin cytoskeleton. Finally, the authors found a co-localization of beta1-integrin with MMP-2 at the leading edge of migrating astrocytes. Altogether, these data provide the first evidence for the implication of MMP-2 in astrocyte motility, probably through the interaction of the proteinase with beta1-integrin that could act as a linker between pericellular proteolysis and the actin cytoskeleton.

show abstract

Section: Proteinase Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Ogier

Bernard

Chollet

et al. 2006

Glia

Self Cite

110

View full text Add to dashboard Cite

show abstract

“…The polystyrene resin functionalized with a 2-chlorotrityl linker can also be used for the parallel synthesis of hydroxamic acids of low molecular weight [171,172] and the solid-phase synthesis according to the Miller hydroxamate approach of peptides modified with a C-terminal b-lactam ring [173]. Alternatively, a polystyrene resin carrying a trityl linker can be used for the solid-phase synthesis of nucleoside hydroxamic acids [153].…”

Section: Super Acid-sensitive Linkersmentioning

confidence: 99%

Hydroxamic Acids: Chemistry, Bioactivity, and Solutionand Solid‐Phase Synthesis

Griffith

Devocelle

Marmion

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

View full text Add to dashboard Cite

“…Indole-4-carboxylic amide derivatives possess a wide range of biological activity including CC chemokine receptor 5 (CCR5) antagonists [39], serotonin (5-HT) subtype 2A receptor antagonists [40], muscarinic M2 receptor antagonists [41], bradycardic agents [42], histone deactylase inhibitors [43], p38α mitogen activated protein kinases (MAPK) inhibitors [44], matrix metalloproteinases (MMPs) inhibitors [45], and poly(ADP-ribose) polymerase-1-inhibitors [46]. Typically indoles of this subclass have been prepared from commercially available indole-4-carboxylic acid or 4-bromoindole [47], both of which are expensive reagents and require extensive manipulation if a more substituted pharmacophore is needed.…”

Section: Preparation Of 2-arylindole-4carboxylic Amide Derivativesmentioning

confidence: 99%

A General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores

Kuethe¹

2006

Chimia

View full text Add to dashboard Cite

the development of a long-term manufacturing route to a potent and selective KDr kinase inhibitor has led to the discovery of several novel methodologies for the general synthesis of indoles. the key transformations involved addition of a trimethylsilylnitro benzene to an aromatic aldehyde which afforded the key nitroalcohol intermediate. oxidation of the nitroalcohol intermediate led to a nitroketone; whereas, elimination afforded exclusively a trans-nitrostyrene. reductive cyclization gave the target compounds in excellent overall yield from readily available bulk chemicals. Application of this methodology has led to the synthesis of highly functionalized pharmacophores including other KDr kinase inhibitors, biindoles and tjipanazole natural products, indolo[2,3-a]pyrrolo [3,4-c]carbazoles, indole-4-carboxylic amides, N-hydroxyindoles, and 2,3-dihydrobenzofurans.

show abstract

Solid-phase synthesis of α-substituted 3-bisarylthio N-Hydroxy propionamides as Specific MMP Inhibitors

Cited by 32 publications

References 23 publications

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Matrix metalloproteinase‐2 (MMP‐2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins

Hydroxamic Acids: Chemistry, Bioactivity, and Solutionand Solid‐Phase Synthesis

A General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores

Contact Info

Product

Resources

About