Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-Isoquinolinylguanidines

Barber, Christopher G.; Dickinson, R. P.; Fish, Paul V.

doi:10.1016/j.bmcl.2004.03.094

Cited by 36 publications

(33 citation statements)

References 26 publications

(15 reference statements)

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“…However, it has not been shown to play any role in cancer metastasis, rather it is a key component of the fibrinolytic cascade and thus considered indispensable. Achievement of adequate selectivity over tPA, and other similar enzymes such as thrombin and plasmin, is therefore an important requirement in a therapeutically valuable uPA inhibitor [13]. The four C. lucidus extracts (0.18 mg/mL) were thus tested for inhibition of equal number of moles (0.002 nmoles) of each of the three enzymes: uPA, tPA and plasmin.…”

Section: Resultsmentioning

confidence: 99%

“…Since antiproteolytic therapy through enzyme inhibition, is one of the preferred strategies for cancer treatment, the uPA system is the obvious choice for manipulation [11,12]. Inhibitors of uPA are thus good candidates for use as drugs in treatment of cancer and also other disease situations where uPA-driven degradation of extra cellular matrix or uPA-dependent cell migration is thought to be important [13]. …”

Section: Introductionmentioning

confidence: 99%

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Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts

et al. 2013

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In view of the clear evidence that urokinase type plasminogen activator (uPA) plays an important role in the processes of tumor cell metastasis, aortic aneurysm, and multiple sclerosis, it has become a target of choice for pharmacological intervention. The goal of this study was thus to determine the presence of inhibitors of uPA in plants known traditionally for their anti-tumor properties. Crude methanol extracts were prepared from the leaves of plants (14) collected from the subtropical dry forest (Guanica, Puerto Rico), and tested for the presence of inhibitors of uPA using the fibrin plate assay. The extracts that tested positive (6) were then partitioned with petroleum ether, chloroform, ethyl acetate and n-butanol, in a sequential manner. The resulting fractions were then tested again using the fibrin plate assay. Extracts from leaves of Croton lucidus (C. lucidus) showed the presence of a strong uPA inhibitory activity. Serial dilutions of these C. lucidus partitions were performed to determine the uPA inhibition IC50 values. The chloroform extract showed the lowest IC50 value (3.52 μg/mL) and hence contained the most potent uPA inhibitor. Further investigations revealed that the crude methanol extract and its chloroform and n-butanol partitions did not significantly inhibit closely related proteases such as the tissue type plasminogen activator (tPA) and plasmin, indicating their selectivity for uPA, and hence superior potential for medicinal use with fewer side effects. In a further evaluation of their therapeutic potential for prevention of cancer metastasis, the C. lucidus extracts displayed cytostatic activity against human pancreatic carcinoma (PaCa-2) cells, as determined through an MTS assay. The cytostatic activities recorded for each of the partitions correlated with their relative uPA inhibitory activities. There are no existing reports of uPA inhibitors being present in any of the plants reported in this study.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts

et al. 2013

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“…It is highly expressed in human cancer and has the ability to prevent apoptosis, stimulate angiogenesis, mitogenesis, cell migration, and to modulate cell adhesion [94]. uPA, one of the hydrolases implicated in the degradation of the extracellular matrix and tumor invasion, is directly inhibited by EGCG [33].…”

Section: Inhibition Of Tumorigenesis and Possible Mechanism: Molecmentioning

confidence: 99%

Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications

Singh

Shankar

Srivastava

2011

Biochemical Pharmacology

1,266

874

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An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of it’s safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and it’s mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

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“…1, Benzoic acid, 3-[1-[(aminoiminomethyl)amino]-4-chloro-7-isoquinolinyl]-,) is a Pfizer compound that has been investigated for the topical treatment of chronic ulcerous wounds by topical administration. It combines inhibition of uPA (Ki of 0.037 M) with a lack of inhibition of the closely related enzyme, tPA, a key part of the fibrinolytic cascade and plasmin [9,10].…”

Section: Introductionmentioning

confidence: 99%

Determination of a potent urokinase-type plasminogen activator, UK-356,202, in plasma at pg/mL levels using column-switching HPLC and fluorescence detection

Bayliss

Venn

Edgington

et al. 2009

Journal of Chromatography B

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Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-Isoquinolinylguanidines

Cited by 36 publications

References 26 publications

Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts

Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts

Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications

Determination of a potent urokinase-type plasminogen activator, UK-356,202, in plasma at pg/mL levels using column-switching HPLC and fluorescence detection

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