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Gohda K.,Computer aided Molecular Modeling Research Center | Fujimori K.,Osaka University of Pharmaceutical Sciences | Teno N.,Hiroshima International University | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University
Chemical Biology and Drug Design | Year: 2014

We here strove to overcome the limitations of expression analyses such as PCR and IHC, based on molecular recognition between target and probe molecules, by designing synthetic substrates specific to the target molecules to directly estimate the enzymatic functionality in situ. The specific substrate contains a probing unit, which is an organic fragment for specific enzyme binding, and a reactive unit, which is a natural peptide subject to catalysis. In this study, the activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells using the plasmin-specific synthetic substrates designed from their inhibitors. The localization and function of the activated plasmin were successfully visualized by fluorophore combined with the specific substrate concurrently. This would be the first time for activated plasmin at work in situ by direct observation. Our concept to directly monitor the functionality of target enzymes can be used straightforwardly for other proteases such as cathepsins or caspases. Also, this substrate concept as a 'tailor-made substrate' would be utilized as a novel functional molecular probe in vivo with appropriate detectable probes. We designed synthetic substrates specific to target molecules to directly estimate enzymatic functionality in situ. It contains a probing unit, an organic fragment specific for enzyme-binding; and a reactive unit, a natural peptide subject to catalysis. In this study, activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells, and the localization and function of plasmin were successfully visualized by fluorophore in the substrate. This would be the first time for activated plasmin at work in situ by direct observation. © 2013 John Wiley & Sons A/S. Source


Hidaka K.,Kobe Gakuin University | Gohda K.,Computer aided Molecular Modeling Research Center | Teno N.,Hiroshima International University | Wanaka K.,Research Projects on Thrombosis and Haemostatsis | Tsuda Y.,Kobe Gakuin University
Bioorganic and Medicinal Chemistry | Year: 2016

Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50 = 0.22 and 77 μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site. © 2015 Elsevier Ltd. All rights reserved. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Sueda T.,Hiroshima International University | Tsuda Y.,Kobe Gakuin University
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9. © 2011 Elsevier Ltd. All rights reserved. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2014

In the development of plasmin inhibitors, a novel chemotype, pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer. © 2014 Elsevier Ltd. All rights reserved. Source


Teno N.,Hiroshima International University | Gohda K.,Computer aided Molecular Modeling Research Center | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Tsuda Y.,Kobe Gakuin University | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin. © 2015 Elsevier Ltd. Source

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