A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis

Wu, Jianhui; Li, Chunyu; Zhao, Ming; Wang, Wenjing; Wang, Yuji; Peng, Shiqi

doi:10.1016/j.bmc.2010.07.043

Cited by 27 publications

(18 citation statements)

References 23 publications

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“…The Boc protection was then removed giving 10b and 11b , which in turn were coupled to 1 to obtain compounds 10a and 11a . 31 The final products 10 and 11 were obtained by removing the benzyl ester protection via hydrogenation.…”

Section: Chemistrymentioning

confidence: 99%

Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

et al. 2013

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The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The L-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small molecule antagonists of the EphA2 receptor.

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Section: Chemistrymentioning

confidence: 99%

Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

et al. 2013

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“…The DNA-intercalating compound β-carboline alkaloid has been synthesized from natural amino acid through condensation reaction, and among all synthesized DNA intercalators,10,11 β-carboline alkaloid is widely used in drug delivery systems and as a DNA intercalation agent 12,13. In a previous study,12 β-carboline derivates were proved to intercalate into DNA double helix and cause DNA damage and inhibit the growth of tumor significantly.…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study,12 β-carboline derivates were proved to intercalate into DNA double helix and cause DNA damage and inhibit the growth of tumor significantly. Meanwhile, they were shown to be biocompatible, non-inflammatory, nontoxic and biodegradable for drug delivery 5.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and evaluation of VEGF-siRNA/CRS as a novel vector for gene delivery

Zhao¹,

Zhang²,

Jiang³

et al. 2016

DDDT

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Small interfering RNA (siRNA) delivery is a prospective method in gene therapy, but it has application limitations such as negative charge, water solubility and high molecular weight. In this study, a safe and efficient nano-vector, CRS, was designed and synthesized to facilitate siRNA delivery. Physical and chemical properties of VEGF-siRNA/CRS were characterized by methods including scanning electron microscopy (SEM), transmission electron microscopy, zeta potential (ζ) measurement, drug-releasing rate measurement, gel electrophoresis and confocal microscopy. The biological activities were evaluated using cell viability assay, gene-silencing efficacy assay in vitro, real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA) and antitumor tests in vivo. The mean nanoparticle size of VEGF-siRNA/CRS was 121.4±0.3 nm with positive ζ potential of 7.69±4.47 mV. The release rate of VEGF-siRNA from VEGF-siRNA/CRS was 82.50% sustained for 48 h in Tris-ethylenediaminetetraacetic acid buffer (pH 8.0). Real-time polymerase chain reaction was used to analyze the efficiency of the transfection, and the result showed that VEGF mRNA expression had been knocked down by 82.36%. The expression of VEGF protein was also recorded to be downregulated to 14.83% using ELISA. The results of cytotoxicity measured by Cell Counting Kit-8 assay showed that VEGF-siRNA/CRS had significant inhibitory effect on HeLa cells. The results of antitumor assays indicated that VEGF-siRNA/CRS exhibited tumor cell growth inhibition in vivo. The results demonstrated that VEGF-siRNA could be delivered and transported by the designed carrier, while siRNA could be released constantly and led to an increasing gene-silencing effect against VEGF gene. In conclusion, VEGF-siRNA/CRS is a promising carrier for siRNA delivery, and further studies are warranted.

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“…23 In vivo Anti-Tumor Assay On S180 mouse model this assay was carried out, and the mice were divided into 7 groups (each 12). 24 The mice in positive control group were intraperitoneally injected doxorubicin (Dox, 2 μmol/kg/day) for 9 consecutive days, the mice in negative control group were orally given CMCNa (carboxymethyl cellulose sodium, 0.5%) for 9 consecutive days, the mice in parent compound control group were orally given ICCA (5 μmol/kg/day) for 9 consecutive days, the mice in modification control group were orally given Trp-Phe-Phe (5 μmol/kg/day) for 9 consecutive days, the mice in object compound group were orally given ICCA-WFF (5, 0.5 and 0.05 μmol/kg/day) for 9 consecutive days.…”

Section: Bioassays In Vitro Anti-proliferation Assaymentioning

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

Self Cite

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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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A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis

Cited by 27 publications

References 23 publications

Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

Design, synthesis and evaluation of VEGF-siRNA/CRS as a novel vector for gene delivery

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

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