Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution

Kubota, Dai; Ishikawa, Minoru; Ishikawa, Midori; Yahata, Naokazu; Murakami, Shoichi; Fujishima, Kazuyuki; Kitakaze, Masafumi; Ajito, Katsuhiro

doi:10.1016/j.bmc.2006.01.062

Cited by 17 publications

(13 citation statements)

References 14 publications

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“…The poly(ethylene glycol) (PEG) derivatives 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethylamine (NH 2 -PEG 4 -N 3 ) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethylmethanesulfonate (MsO-PEG 4 -N 3 ) were synthesized according to recently described procedures . Lead compound 5 was synthesized as shown in Scheme and reported in the literature . The RGD peptide used for blocking studies ( cyclo -[C RGD C]GK) was purchased from Bachem (Bubendorf, Switzerland) and has been used before. , Nuclear magnetic resonance (NMR) spectra ( 1 H, 13 C and 19 F) were recorded on a Bruker AV 300 or AV 400 instrument (Bruker BioSpin GmbH, Rheinstetten, Germany) or an Agilent DD2 600 instrument (Agilent Technologies Deutschland GmbH, Boeblingen, Germany), respectively.…”

Section: Methodsmentioning

confidence: 99%

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Alsibai¹,

Hahnenkamp²,

Eisenblätter

et al. 2014

J. Med. Chem.

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Integrins are heterodimeric transmembrane protein receptors consisting of different α and β subunits. α(v)β(3) integrins are overexpressed on many tumor cells and tumor-associated angiogenic vessels, whereas α(IIb)β(3) is a receptor for, e.g., fibrinogen and mediates platelet aggregation. In this study, a near-infrared fluorescent imaging probe has been designed and synthesized by conjugating fluorescent dyes to a non-peptidic, pharmacophore-based ligand, based on a molecular modeling design approach. Affinity values were determined, and in vitro cell binding assays and preliminary in vivo xenograft studies in nude mice were performed to evaluate target binding. Competition assays revealed excellent binding and selectivity to α(v)β(3) compared to that for α(IIb)β(3). In vitro, the probe showed high target binding on α(v)β(3)-positive M-21 cells and negligible binding to α(v)β(3)-negative MCF-7 cells. In vivo, the tracer is able to image target expression in U-87 xenografts with a maximum signal-to-noise ratio (SNR) of 2.5:1 at 24 h after injection.

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Section: Methodsmentioning

confidence: 99%

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Alsibai¹,

Hahnenkamp²,

Eisenblätter

et al. 2014

J. Med. Chem.

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“…CP4715, an α V β 3 integrin inhibitor, was prepared as previously described [18][19][20][21]. In some experiments, MRC-5 cells and IPF lung fibroblasts were treated with 1 μM CP4715 dissolved in DMSO for 24 h.…”

Section: Transient Transfectionmentioning

confidence: 99%

Periostin plays a critical role in the cell cycle in lung fibroblasts

et al. 2020

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Background: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5 years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation.Methods: In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin α V β 3 (a periostin receptor), which we have recently found blocks TGF-β signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients.Results: Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cyclerelated molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts.Conclusions: Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin α V β 3 interaction for the treatment of IPF patients.

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“…Discarding those compounds with unspecified antagonistic activity and the chemicals with undefined stereochemistry, a total of 102 tricyclic piperazine or piperidine furnished molecules with a wide spectrum of antiplatelet activities against dual ␣ v ␤ 3 and ␣ IIb ␤ 3 receptors were collected from the work of D. Kubota et al and used as the dataset for molecular modeling in this study [2,10,24,25]. In this work, the in vitro biological activities of these compounds were converted into the corresponding pIC 50 (−log IC 50 ) values, which were used as dependent variables in the QSAR analyses.…”

Section: Dataset and Biological Activitymentioning

confidence: 99%

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking

Yan

Zhang

et al. 2011

Journal of Molecular Graphics and Modelling

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Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution

Cited by 17 publications

References 14 publications

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Periostin plays a critical role in the cell cycle in lung fibroblasts

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking

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Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution

Cited by 17 publications

References 14 publications

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for αVβ3vs αIIbβ3Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for αVβ3vs αIIbβ3Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Periostin plays a critical role in the cell cycle in lung fibroblasts

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking

Contact Info

Product

Resources

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Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging

Fluorescent Non-peptidic RGD Mimetics with High Selectivity for α_Vβ₃vs α_IIbβ₃Integrin Receptor: Novel Probes for in Vivo Optical Imaging