N-i-Propoxy-N-biphenylsulfonylaminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP

Rossello, Armando; Nuti, Elisa; Carelli, Paolo; Orlandini, Elisabetta; Macchia, Marco; Nencetti, Susanna; Zandomeneghi, Maurizio; Balzano, Federica; Barretta, Gloria Uccello; Albini, Adriana; Benelli, Roberto; Cercignani, Giovanni; Murphy, Gillian; Balsamo, Aldo

doi:10.1016/j.bmcl.2005.01.024

Cited by 38 publications

(20 citation statements)

References 38 publications

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“…(That both enantiomers bind more tightly than the racemate is, however, a conundrum that Sani et al are addressing.) The N-isopropoxy substituted compound 849773-63-3 [84] incorporates recognizable MMI-270 and PD-166793 features and is MMP-1 sparing (MT1-MMP, 15-fold selective and MMP-2, 1500-fold selective against MMP-1). Each of the remaining structures presents a new structural advance in MMP inhibitor design, albeit at the cost of increased structural and stereochemical complexity.…”

Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

Recent advances in MMP inhibitor design

Fisher

Mobashery

2006

Cancer Metastasis Rev

239

205

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The search for an MMP inhibitor with anticancer efficacy is a nearly three-decade endeavor. This inhibitor is yet to be found. The reasons for this failure include shortcomings in the chemistry of these compounds (including broad MMP sub-type selectivity, metabolic lability, and toxicity) as well as the emerging, and arguably extraordinary, complexity of MMP cell (and cancer) biology. Together these suggest that the successful anticancer inhibitor must possess MMP selectivity against the MMP subtype whose involvement is critical, yet highly temporally (with respect to metastatic progression) and mechanistically (with respect to matrix degradation) regulated. This review summarizes the progression of chemical structure and mechanistic thinking toward these objectives, with emphasis on the disappointment, the perseverance, and the resilient optimism that such an inhibitor is there to be discovered.

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Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

Recent advances in MMP inhibitor design

Fisher

Mobashery

2006

Cancer Metastasis Rev

239

205

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“…In an aim to improve the potency of some molecules towards MMP-2 and MMP-9, and also towards MMP-14, Rossello et al developed some new N-i-propoxy-Nbiphenylsulfonylaminobutylhydroxamic acids in the class of MMPIs [94]. In these new type hydroxamates 17 ( Table 2), they have introduced some alkyl substituents possessing an increasing steric bulkiness and lipophilicity in R 2 , this new R 2 substitution site strongly favoured lipophilic interactions with the nearby S1 region of the enzyme site, reinforcing the binding of the planned new inhibitors to the active site of MMP-2 and MMP-14.…”

Section: Ophmentioning

confidence: 99%

Selective Matrix Metalloproteinase Inhibitors for Cancer

Li¹,

Shi²,

Tang³

et al. 2009

CMC

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The matrix metalloproteinases are a family of nearly 30 enzymes that are intimately involved in tissue remodeling. Disease processes associated with the matrix metalloproteinases are generally related to imbalance between the inhibition and activation of matrix metalloproteinases resulting in excessive degradation of the extracellullar matrix. These include osteoarthritis, rheumatoid arthritis, tumor metastasis and congestive heart failure. Despite massive research and development efforts, there are only two drugs launched on the market: periostat (doxycycline), a tetracycline used for periodontal disease and glucosemine sulfate, for osteoarthritis. Possible reasons for the low success rate of matrix metalloproteinase inhibitors in the clinic are mainly from unwanted side effects caused by their lack of selectivity, since inhibition of collagenase-1 may be responsible for the musculoskeletal side effects observed clinically with broad-spectrum inhibitors. Considering these data, many efforts were directed to developing a more selective second generation of inhibitors against the specific matrix metalloproteinases believed to be involved in the different pathologies. This review mainly focuses on selective matrix metalloproteinase inhibitors development on matrix metalloproteinases in terms of antitumor since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, natural products and their derivatives. Through these methods, new hope is emerging in the form of synthetic and natural matrix metalloproteinase inhibitors for the prevention and treatment of cancer.

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“…The compounds ARP101, EN178, LM2 and FC19 were synthesised as previously reported [21][22][23][24]. Compound EN204 was prepared as described in Scheme 1.…”

Section: Chemistrymentioning

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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N-i-Propoxy-N-biphenylsulfonylaminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP

Cited by 38 publications

References 38 publications

Recent advances in MMP inhibitor design

Recent advances in MMP inhibitor design

Selective Matrix Metalloproteinase Inhibitors for Cancer

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

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