Phosphinic Pseudo-Tripeptides as Potent Inhibitors of Matrix Metalloproteinases:  A Structure−Activity Study

Vassiliou, Stamatia; Mucha, Artur; Cuniasse, Philippe; Georgiadis, Dimitris; Lucet-Levannier, Karine; Beau, Fabrice; Kannan, Rama; Murphy, Gillian; Knäuper, Vera; Rio, Marie‐Christine; Basset, Paul; Yiotakis, Athanasios; Dive, Vincent

doi:10.1021/jm9900164

Cited by 113 publications

(125 citation statements)

References 49 publications

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“…29 Enzyme inhibition assays were carried out in 50 mM Tris/HCl buffer, pH 6.8, CaCl 2 at 25°C and Ki values were determined. 26 Pharmacokinetics, metabolism and balance of elimination of RXP03.R FI Fifteen days after C 26 cell s.c. injection, 36 female BALB/c mice bearing tumors were randomly divided into 2 groups: 1 group for pharmacokinetic study (32 animals, PK-TD group) and the other for the study of the balance of elimination (4 animals, Bal-MET). Each animal received labeled 3 H-RXP03.R FI , suspended in PBS (1 ϫ) solution containing 3% DMSO by intraperitoneal (i.p.)…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…In vitro effect of RXP03.R FI on C 26 cell culture C 26 cells were derived from colon carcinomas induced in BALB/c mice by repeated intrarectal instillations of N-nitroso-Nmethylurethane and exhibited an in vivo doubling time of 1.7 days. 30 For in vitro proliferation assay, C 26 cells were plated in triplicate into 24-microwell plates (2 ϫ 10 4 cells/well), and subconfluent cultures were treated with 3 M RXP03.R FI diluted in 1 ϫ PBS.…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…[23][24][25] We previously reported a series of potent phosphinic peptide inhibitors of MMPs. 26 One of these compounds, RXP03 ( Fig. 1), showing selectivity for MMP-11, MMP-8 and MMP-13, was selected to evaluate its antitumor efficacy.…”

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confidence: 99%

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Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Dive

Andarawewa

Boulay

et al. 2004

Intl Journal of Cancer

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The in vivo disposition and antitumor efficacy of a newly developed phosphinic matrix metalloproteinase inhibitor (RXP03) were examined. RXP03 potently inhibits MMP-11, MMP-8 and MMP-13, but not MMP-1 and MMP-7. Twenty-four hours after i.p. injection into mice, most of the RXP03 was recovered intact in plasma, feces (biliary excretion) and tumor tissue. Pharmacokinetic parameters indicated that, after an i.p. dose of 100 g/day, the plasma concentration of RXP03 over 24 hr remained higher than the Ki values determined for MMP-11, MMP-8 and MMP-13. Efficacy of RXP03 on the growth of primary tumors induced by s.c. injection of C 26 colon carcinoma cells in mice was observed to depend both on RXP03 doses and treatment schedules. Tumor volumes in mice treated for 18 days with 50, 100 and 150 g/day of RXP03 were decreased compared with control tumor volumes, 100 g/day being the most effective dose. Treatment at higher dose (600 g/day) did not significantly reduce the tumor size as compared to control. Short treatments with RXP03 100 g/day, 3 to 7 days after C 26 inoculation, were more effective on tumor growth than continuous treatment over 18 days. Strikingly, RXP03 treatment started 6 days after the C 26 injection and continued until day 18 led to stimulation of tumor growth, as compared to control. These paradoxical effects, depending on the RXP03 treatment schedule, underline the need to define carefully the spatiotemporal function of each MMP at various stages of tumor growth to achieve optimal therapeutic effects by MMP inhibitor treatment.Key words: phosphinic peptides; matrix metalloproteinase Matrix metalloproteinases (MMPs) have been recognized since the early 1980s as promising targets for cancer therapy on the basis of their overexpression at different stages of tumor progression 1,2 and their unique ability to degrade all components of the extracellular matrix. 3 However, the range of protein substrates cleaved by MMPs is far more complex than previously anticipated and new functions of MMPs with relevance for cancer have recently emerged. 4,5 Cell surface receptor shedding, 6,7 cytokine activation, 8 -10 chemokine inactivation, 11 release of apoptotic or antiapoptotic signals, 12,13 regulation of angiogenesis 14 and immune surveillance 11,15 are examples of molecular events mediated by MMPs. These different functions led to the current view that MMPs not only support tumor growth, but also participate in host defense. These apparently contrasting functions of MMPs during tumor progression may in part explain why clinical trials with broad-spectrum MMP inhibitors have yielded disappointing results. 16,17 These results emphasize the need to determine the different roles of MMPs in specific stages of tumor progression. 18 In addition, more specific MMP inhibitors should be developed and tested.Phosphinic pseudopeptides represent a new class of potent inhibitors of zinc metalloproteinases. 19 Screening of phosphinic inhibitor libraries prepared by combinatorial chemistry led to the identification of highly s...

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Section: Enzyme Assaysmentioning

confidence: 99%

Section: Enzyme Assaysmentioning

confidence: 99%

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Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Dive

Andarawewa

Boulay

et al. 2004

Intl Journal of Cancer

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“…Finally, the saponification of the methyl ester followed by the cleavage of the N-Cbz bond with BBr 3 and the semipreparative HPLC purification, provided the enantiomerically pure phosphinic pseudopeptide (R,S,S)-81 in 92% yield (Scheme 34). In a related work, Samios et al [78] developed an efficient synthetic methodology for the preparation of the phosphinic pseudotripeptide known as RXP03, which has been widely studied as MMPs inhibitor [79,80]. Initially, reaction of the N-Cbz H-phosphinic acid analogue of phenylalanine (R)-66a [72] with bis(trimethylsilyl)amine (HMDS) followed by the addition of ethyl phenylpropylacrylate and subsequent hydrolysis of the ethyl ester group, gave C-phosphinate 82 in 90% yield, which by coupling with (S)-TrpNH2, afforded the phosphinic pseudotripeptides (R,S,S)-83 and (R,R,S)-84 in 77% yield, which were separated in 99% purity by preferential precipitation in EtOH (Scheme 35).…”

Section: Scheme 32 Synthesis Of the C-phosphinic Acid 75 And Its Actmentioning

confidence: 99%

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

et al. 2016

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α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed.

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“…In mouse models, its expression induces tumour implantation and its proteolytic activity is essential to enhance tumorigenicity 4 . Therefore ST3 represents an attractive therapeutical target and selective phosphinic inhibitors have been developed 5 .…”

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confidence: 99%

Structural changes at the copper centre of Azurin in an oxidation-reduction process: an integrated approach combining crystallography and EXAFS

Dodd¹,

Cheung²,

Strange³

et al. 2000

Acta Cryst Sect A

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Crystallographic structures of oxidised and reduced forms of azurin II are reported at 1.75~ resolution [1]. Data were collected using one crystal in each case and by translating crystal after each oscillation range to minimise photo-reduction. Very small differences are observed at the Cu site upon reduction and that these cannot be determined with confidence at current resolution. A comparison with the 3D EXAFS reveals a good correspondence for all the ligands distances except for CuHis46 where a larger deviation of ~0.12-0.18~ is observed indicating that this ligand is more tightly restrained in the crystallographic refinement at the current resolution. Three dimensional information is obtained for the Cu site in azurin [2] at very high resolution by combining high resolution crystallographic structures and EXAFS data for the oxidised and reduced form of the protein. This combined approach has allowed us to define the subtle structural changes (<0.1~) which take place at the Cu site during a single electron redox process. s8a.m7.p14.la Crystal structure of the Stromelysin-3 complexed with a phosphinic inhibitor reveals that its S 1 ' pocket is a deep opened cavity. A

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Phosphinic Pseudo-Tripeptides as Potent Inhibitors of Matrix Metalloproteinases: A Structure−Activity Study

Cited by 113 publications

References 49 publications

Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

Structural changes at the copper centre of Azurin in an oxidation-reduction process: an integrated approach combining crystallography and EXAFS

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