Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor

Wang, Xiaozhen; Wang, Yuji; Wu, Jianhui; Gui, Lin; Zhang, Xiaoyi; Zheng, Meiqing; Wang, Yaonan; Zhao, Shunying; Li, Ze; Zhao, Ming; Peng, Shiqi

doi:10.1016/j.bmcl.2017.10.068

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…To perform docking investigation, the conformation of β-carboxylic acids and their benzyl esters was generated by following the literature. 20 , 21 According to the literature, 10 energy-optimized conformations of each β-carboxylic acid and benzyl ester were docked into the active sites of P-selectin and GPIIb/IIIa with CDOCKER protocol and using the procedure of the literature. 20 , 21 …”

Section: Methodsmentioning

confidence: 99%

“…In this context, the structural characteristics of the previously reported carbolines were analyzed. These carbolines inhibited arterial thrombosis; 19 targeted GPIIb/IIIa receptor thereby inhibited arterial thrombosis; 20 targeted P-selectin receptor thereby inhibited arterial thrombosis and venous thrombosis, 21 slowed down tumor growth, 22 , 25 , 26 or simultaneously inhibited thrombosis and slowed down tumor growth; 22 , 23 or targeted P-selectin receptor thereby simultaneously inhibited arterial thrombosis and slowed down tumor growth. 24 The findings led to 10 known carbolines been docked into the active pockets of P-selectin and GPIIb/IIIa receptors.…”

Section: Introductionmentioning

confidence: 99%

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Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

Chen

Zhang

et al. 2018

DDDT

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BackgroundThe impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth.MethodsFor this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-β-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors.ResultsThe synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver.ConclusionTherefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

Chen

Zhang

et al. 2018

DDDT

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“…For this purpose, the conformations of ICCA-WFF and ICCA were generated, and 10 energy optimized conformations of ICCA-WFF and ICCA were docked into the active sites of P-selectin and GPIIb/IIIa with CDOCKER protocol and using the procedure of the literature. 26,30 Molecular Assembly and Thrombus Targeting Action…”

Section: Testing Pt Tt Aptt and Fibmentioning

confidence: 99%

<p>Modifying ICCA with Trp-Phe-Phe to Enhance in vivo Activity and Form Nano-Medicine</p>

Zhang

Wang

et al. 2020

IJN

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Background: 1-(4-isopropylphenyl)-β-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-β-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). Purpose: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. Methods: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. Results: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. Conclusion: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.

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“…Carboline alkaloid is an active ingredient extracted from traditional Chinese medicine. Our group has conducted in-depth research on its antitumor and other activities (16,17). Many studies have combined carboline and its derivatives with ruthenium to obtain a series of antitumor active compounds (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

A Dual-Targeting Ruthenium Nanodrug that Inhibits Primary Tumor Growth and Lung Metastasis by the PARP/ATM Pathway

Zhu

Gui

et al. 2020

Preprint

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Many studies have found that ruthenium complexes have unique biochemical characteristics and thus inhibit tumor growth or metastasis. Our aim was to report a novel dual-targeting ruthenium candidate 2b with both antitumor and antimetastatic functions that could target tumor sites using both EPR effects and TF/TFR. It was composed of ruthenium-complexed carboline acid and four chloride ions. In vitro, 2b could trigger DNA cleavage and thus block the cell cycle and cause apoptosis by the PARP/ATM pathway. In vivo, 2b could inhibit not only LLC tumor growth but also lung metastasis. We found apoptosis and decrease in CD31 expression in tumor tissue. In addition, we also found that 2b could collect in tumor tissue. Thus, we concluded that 2b could target tumors, inhibit tumor growth and prevent lung metastasis.

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Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor

Cited by 5 publications

References 26 publications

Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

<p>Modifying ICCA with Trp-Phe-Phe to Enhance in vivo Activity and Form Nano-Medicine</p>

A Dual-Targeting Ruthenium Nanodrug that Inhibits Primary Tumor Growth and Lung Metastasis by the PARP/ATM Pathway

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