Synthesis and biological activity of peptidyl aldehyde urokinase inhibitors

Tamura, Shigeki; Weinhouse, Michael I.; Roberts, Christopher A; Goldman, Erick A.; Masukawa, Kevin M.; Anderson, Seth C.; Cohen, Cheryl R.; Bradbury, Annette E; Bernardino, Vernon; Dixon, S.A.; Ma, Michael G; Nolan, Thomas G.; Brunck, Terence K.

doi:10.1016/s0960-894x(00)00149-9

Cited by 28 publications

(26 citation statements)

References 19 publications

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“…The synthesis of peptidyl aldehydes (20) and ␣-ketoamides (14) was accomplished essentially as previously described (20). Synthetic details of individual compound synthesis were as previously described (M. Lim-Wilby, J. E. Semple, G. L. Araldi, E. A. Goldman, and M. I. Weinhouse, 20 June 2000, Patent Cooperation Treaty application WO02/ 48097A1).…”

Section: Methodsmentioning

confidence: 99%

Antimalarial Activities of Novel SyntheticCysteine ProteaseInhibitors

Lee

Singh

Chiang³

et al. 2003

Antimicrob Agents Chemother

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Among promising new targets for antimalarial chemotherapy are the cysteine protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the activities of synthetic peptidyl aldehyde and ␣-ketoamide cysteine protease inhibitors against these proteases, against cultured Plasmodium falciparum parasites, and in a murine malaria model. Optimized compounds inhibited falcipain-2 and falcipain-3, blocked hemoglobin hydrolysis, and prevented the development of P. falciparum at nanomolar concentrations. The compounds were equally active against multiple strains of P. falciparum with varied sensitivities to standard antimalarial agents. The peptidyl inhibitors were consistently less active against vinckepain-2, the putative falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite Plasmodium vinckei. The lead compound morpholinocarbonyl-leucinehomophenylalanine aldehyde, which blocked P. falciparum development at low nanomolar concentrations, was tested in a murine P. vinckei model. When infused continuously at a rate of 30 mg/kg of body weight/day, the compound delayed the progression of malaria but did not eradicate infections. Our data demonstrate the potent antimalarial activities of novel cysteine protease inhibitors. Additionally, they highlight the importance of consideration of the specific enzyme targets of animal model parasites. In the case of falcipains, differences between P. falciparum and rodent parasites complicate the use of the rodent malaria model in the drug discovery process.

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Section: Methodsmentioning

confidence: 99%

Antimalarial Activities of Novel SyntheticCysteine ProteaseInhibitors

Lee

Singh

Chiang³

et al. 2003

Antimicrob Agents Chemother

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“…Libraries of structurally related peptide derivatives were synthesized and tested for uPA inhibition. The most potent peptide inhibitor of uPA (Phenethylsulfonyl-D-Ser-AlaArginal) exhibited a 100-fold selectivity for uPA over plasmin, and greater than an 800-fold selectivity for uPA over tPA [241]. The nanomolar range of potencies for some of the amino acid-based uPA inhibitors illustrates the potential for small molecules to inhibit uPA competitively and with high selectivity, and provides a guide to the design of many potent, non-peptide small molecule uPA inhibitors [reviewed in ref .…”

Section: The Plasminogen Activator System and I T S D O W N S T R E Amentioning

confidence: 99%

Targeting Invasion Induction as a Therapeutic Strategy for the Treatment of Cancer

Livant

2005

CCDT

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The spread of cancer cells from the primary tumor to a distant site involves many of the invasive processes normally required for wound healing, including migration through the local connective tissue, invasion of the vasculature, extravasation, invasion of the connective tissue at a distant site, and angiogenesis. Thus, the abilities of tumor cells to invade the host, and to induce endothelial cell invasion and neovascularization, are central to malignant progression. The plasminogen activator system, which plays a direct role in stimulating alpha5beta1 integrin fibronectin receptor-mediated invasion during wound healing, is also very important in tumor cell invasion and metastasis, as well as in angiogenesis. Therefore, the alpha5beta1 receptor and the plasminogen activator system may be promising targets for directed anticancer therapies.

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“…Corvas has described several substituted phenylpropionic acid derivatives as effective PAI-1 antagonists (Tamura et al 2000). High levels of PAI-1 have been suggested as one of the factors that contribute a poor prognosis for cancer patients (Binder and Mihaly 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Glu-Gly-Arg-CH 2 Cl is a synthetic inhibitor which inhibits urokinase with K i value 5 μM and alkylates the active-site histidine of urokinase (Lijnen et al 1987). But the most active peptide uPA inhibitor is phenethylsulfonyl- d -Ser-Ala-Arg-H with IC 50 value of 3.1 nM (Tamura et al 2000). …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Activity of N-Sulfonyltripeptides with C-Terminal Arginine as Potential Serine Proteases Inhibitors

Markowska

Bruzgo

Gorodkiewicz

et al. 2012

Int J Pept Res Ther

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Tripeptides of the general X-SO2-d-Ser-AA-Arg-CO-Y formula, where X = α-tolyl, p-tolyl, 2,4,6-triisopropylphenyl; AA = alanine, glycine, norvaline and Y = OH, NH-(CH2)5NH2 were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. The most active compound towards urokinase was PhCH2SO2-d-Ser-Gly-Arg-OH with Ki value 5.4 μM and the most active compound toward thrombin was PhCH2SO2-d-Ser-NVa-Arg-OH with Ki value 0.82 μM. The peptides were nontoxic against porcine erythrocytes in vitro. PhCH2SO2-d-Ser-Gly-Arg-OH showed cytotoxic effect against DLD cell lines with IC50 values of 5 μM. For the highly selective determination of the interaction of some of the synthesised acids of tripeptides with urokinase and plasmin the Surface Plasmon Resonance Imaging sensor has been applied. These compounds bind to urokinase and plasmin in 0.05 mM concentration.

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Synthesis and biological activity of peptidyl aldehyde urokinase inhibitors

Cited by 28 publications

References 19 publications

Antimalarial Activities of Novel SyntheticCysteine ProteaseInhibitors

Antimalarial Activities of Novel SyntheticCysteine ProteaseInhibitors

Targeting Invasion Induction as a Therapeutic Strategy for the Treatment of Cancer

Synthesis and Biological Activity of N-Sulfonyltripeptides with C-Terminal Arginine as Potential Serine Proteases Inhibitors

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