Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating arylsulfonylureido and 5-dibenzo-suberenyl/suberyl moieties (original) (raw)
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Journal of Enzyme Inhibition and Medicinal Chemistry, 2003
Novel matrix metalloproteinase (MMP)/bacterial collagenase inhibitors are reported, considering the sulfonylated amino acid hydroxamates as lead molecules. A series of compounds was prepared by reaction of arylsulfonyl isocyanates with N-(5H-dibenzo[a,d]cyclohepten-5-yl)-and N-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl) methyl glycocolate, respectively, followed by the conversion of the COOMe to the carboxylate/hydroxamate moieties. The corresponding derivatives with methylene and ethylene spacers between the polycyclic moiety and the amino acid functionality were also obtained by related synthetic strategies. These new compounds were assayed as inhibitors of MMP-1, MMP-2, MMP-8 and MMP-9, and of the collagenase isolated from Clostridium histolyticum (ChC). Some of the new derivatives reported here proved to be powerful inhibitors of the four MMPs mentioned above and of ChC, with activities in the low nanomolar range for some of the target enzymes, depending on the substitution pattern at the sulfonylureido moiety and on the length of the spacer through which the dibenzosuberenyl/suberyl group is connected with the rest of the molecule. Several of these inhibitors also showed selectivity for the deep pocket enzymes (MMP-2, MMP-8 and MMP-9) over the shallow pocket ones MMP-1 and ChC. #
Bioorganic & medicinal …, 2005
Starting from the observation that the CbzNH(CH 2 ) 2 side chain of the potent MMP-2/MMP-14 inhibitor, benzyl-(3R)-4-(hydroxyamino)-3-[isopropoxy(1,1 0 -biphenyl-4yl-sulfonyl)amino]-4-oxobutylcarbamate, (R)-1 lies in a hydrophobic region (S1) exposed to the solvent of the protease active site, we hypothesized that an aminoethylcarboxamido chain structurally related to that of (R)-1 might be an useful tool to bind another linker stretching out from the protein. This would be able to interact either with a enzyme region adjacent to the active site, or with other molecules of matrix metalloproteinases (MMPs), or other proteins of the extracellular matrix (ECM) that may be involved in the enzyme activation. On these basis we describe new dimeric compounds of type 2, twin hydroxamic acids, obtained by the joint of two drug entities of (R)-1 linked in P1 by extendable semirigid linkers. Type 2 compounds are potentially able to undergo more complex inhibitor-enzyme interactions than those occurring with monomeric compounds of type 1, thus influencing positively the potency, selectivity and/or cytotoxicity of the new compounds.
Bioorganic & Medicinal Chemistry Letters, 1999
Polymer-supported reagents and sequestering agents may be used to generate an array of variously substituted hydroxamic acid derivatives as potential inhibitors of matrix metalloproteinases without any chromatographic purification step. Introduction: Hydroxamic acid derivatives exhibit a variety of pharmaceutical properties, of which their inhibitory effect on the matrix metalloproteinase (MMP) class of enzymes is probably the most important. These enzymes are mediators for the breakdown of structural proteins of the extracellular matrix. Their proposed pathogenic role includes the destruction of cartilage and bone in rheumatoid and osteoarthritis as well as tissue breakdown, metastasis and tumour angiogenesis. During the past years extensive synthesis programmes have focussed on the development of synthetic MMP inhibitors. Screening libraries revealed non-peptidic inhibitors of stromelysin-I (MMP-3) leading to the development of compound 1 (Figure 1) which shows its best results in the inhibition of gelatinase B (MMP-9). y -o.
Journal of Medicinal Chemistry, 2001
A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed ∼90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.
In silico Identification of New Antiproliferative Compounds, Inhibitors of Matrix Metalloproteinases
Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj Napoca Veterinary Medicine, 2011
Tenascin C (TNC) is a glycoprotein of the extracellular matrix and its overexpression induced by matrix metalloproteinases (MMPs) is associated with the amplification of the proliferative response to growth factors, promotion of cancer cell invasion and tumoral growth. This paper looks forward to find better inhibitors of MMPs, based on structure of batimastat (BAT)a synthetic inhibitor of MMPs and an experimental drug against matrix metalloproteinase-16 (MMP16). To reach this aim, at first it was built a complete virtual library using 12 scaffolds (SCs) from BAT, concatenated via a dummy linker with 40 building blocks (BBs) found in 14 antineoplastic drugs. Second, all the derivatives from the virtual library were filtered, through mass-computation, for "drug-likeness", undesirable moieties and checked if they are PAINS (Pan Assay Interference Compounds). At last, a virtual screening of "drug-like" virtual derivatives, free of undesirable moieties (except of the thiophene moiety) and BAT against the homologue model of MMP16 was made, using docking software in order to identify the compounds that specifically bind the enzyme. In the same time it was determinate the smallest binding energy required to bind MMP-16 to reveal the best ligands. Results show that 86 virtual derivates (1% of the 6720 derivates from the virtual library) are "drug-like" compounds. However, only 23 of the "drug-like" virtual derivates have better metrics than BAT, are free of undesirable moieties and are not PAINS. In addition, 15 of them are better ligands for MMP16 than BAT.
Design and synthesis of novel metalloproteinases inhibitors
2009
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)-and (À)-malic acid, and D D-and L L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (À)-malic acid. Structure-activity relationship study is presented.
Bioorganic & Medicinal Chemistry Letters, 2001
A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7.Carboxylic acids prepared from 1,3- and 1,4-cyclohexylglycine scaffolds exhibited efficacy as selective matrix metalloproteinase (MMP) inhibitors.
Bioorganic & Medicinal Chemistry, 2019
Collagen degradation and proMMP-2 activation are major functions of MT1-MMP to promote cancer cell invasion. Since both processes require MT1-MMP homodimerization on the cell surface, herein we propose that the use of bifunctional inhibitors of this enzyme could represent an innovative approach to efficiently reduce tumor growth. A small series of symmetrical dimers derived from previously described monomeric arylsulfonamide hydroxamates was synthesized and tested in vitro on isolated MMPs. A nanomolar MT1-MMP inhibitor, compound 6, was identified and then submitted to cell-based assays on HT1080 fibrosarcoma cells. Dimer 6 reduced MT1-MMP-dependent proMMP-2 activation, collagen 2 degradation and collagen invasion in a dose-dependent manner with better results even compared to its monomeric analogue 4. This preliminary study suggests that dimeric MT1-MMP inhibitors might be further developed and exploited as an alternative tool to reduce cancer cell invasion.
Hydroxamate-based peptide inhibitors of matrix metalloprotease 2
Biochimie, 2005
There is major interest in designing inhibitors for matrix metalloproteinase 2 (MMP-2, gelatinase A) since this enzyme is known to be involved in pathological processes such as tumor invasion or rheumatoid arthritis. The majority of MMP-2 inhibitor candidate drugs block the active site of MMP-2 by binding to its catalytic Zn 2+ ion through a chelating (hydroxamate, sulphonate etc.) group. Despite the general interest in designing MMP-2 inhibitors, the results with many of the drug candidates were disappointing, their failure was usually explained by cross-reactions with other MMPs. One way to enhance MMP-2 selectivity is to design inhibitors that interact with both the active site and exosites such as the fibronectin type II (FN2) domains of the enzyme. In the present work, we have examined the inhibitory potential and MMP-2 selectivity of hydroxamates of three groups of peptides known to bind to the collagen-binding FN2 domains of MMP-2. The first type of peptides consisted of collagen-like (Pro-Pro-Gly) n repeats, peptides of the second group were identified from a random 15-mer phage display library based on their binding to immobilized FN2 domains of MMP-2. A hydroxamate of peptide p33-42, known to bind to the third FN2 domain of MMP-2 has also been tested. Our studies have shown that these compounds inhibited MMP-2 with IC 50 values of 10-100 µM. The fact that their inhibitory potential was nearly identical for MMP-2del, a recombinant version of MMP-2 that lacks the FN2 domains, suggests that inhibition is not mediated by their binding to FN2 domains. It seems likely that the failure to exploit interaction with the FN2 domains is due to the fact that the FN2 domains and the catalytic domain of MMP-2 tumble independently, therefore only a tiny fraction of the conformational isomers can bind peptide hydroxamates via both the active site and the FN2 domain(s).