Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(<scp>iii</scp>) metal-based compound

Lou, Lijuan; Wang, Wanhe; Huang, Sheng-Lung; Hong, Yanjun; Li, Guodong; Lin, Sheng; Tian, Jinglin; Cai, Zongwei; Wang, Hui‐Min David; Leung, Chung‐Hang

doi:10.1039/c7sc00311k

Cited by 117 publications

(70 citation statements)

References 42 publications

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“…Organometallic transition metal‐based complexes exhibit a wide range of applications for the design of antitumor drugs due to their potential redox features, diverse structural types and varied ligand bonding modes . Organometallic complexes of the group VIIIB elements platinum, ruthenium, osmium, rhodium, palladium and iridium have received much attention as potential antitumor agents . Following the clinical success of platinum‐based antitumor drugs such as cisplatin, carboplatin and oxaliplatin, metal‐mediated antitumor drugs have attracted wide attention in chemotherapeutic research .…”

Section: Introductionmentioning

confidence: 99%

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Kong

Guo

Tian

et al. 2018

Applied Organom Chemis

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Fifteen organometallic Ir(III) half-sandwich complexes (1A-5C) having the general formula [(η 5 -Cp x )Ir(N^N)Cl]PF 6 (Cp x = Cp*, tetramethyl(phenyl) cyclopentadienyl (Cp xph ) or tetramethyl(biphenyl)cyclopentadienyl (Cp xbiph ); N^N = diamine) have been synthesized and characterized. The molecular structure of 1A was determined using single-crystal X-ray diffraction analysis.The hydrolysis of 1A-5C was monitored using UV-visible spectra. Complexes 3A-3C showed catalytic activity for the oxidation of NADH to NAD + , where 3C showed the highest turnover number of 29.9 within 450 min. Cytotoxicity examination by MTT assay was carried out against two human cancer cell lines (HeLa and A549) after 24 or 48 h drug treatment. The complexes showed high potency, where the most potent complex (3C; IC 50 = 3.4 μM) was six times more active than cisplatin against A549 cells after 24 h drug exposure. Cytotoxic potency towards A549 cells increased with phenyl substitution on Cp ring: Cp xbiph > Cp xph > Cp*. In addition, the biological studies showed that 3C caused cell apoptosis and cell cycle arrest at G 1 phase in A549 cancer cells.Moreover, 3C increased the level of reactive oxygen species markedly after 24 h, which may provide an important basis for killing cancer cells. Confocal laser scanning microscopy was used to track 3C in A549 cells. The cellular localization experiment showed that 3C targeted lysosomes and caused lysosomal damage.

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Section: Introductionmentioning

confidence: 99%

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Kong

Guo

Tian

et al. 2018

Applied Organom Chemis

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“…As highlighted above, fragment-based screening, computational analysis, and molecular inhibitor design are some of the techniques that have been used in PPI inhibitor development in drug discovery, including in the oncology field [106][107][108][109][110]. Such methods can accelerate the early phases of drug discovery by identifying PPIs as drug targets, followed by physicochemical and topographical characterization of their binding interfaces as well [13,111,112]. A number of (mostly non-covalent) PPI inhibitors have already been approved or entered clinical trials for the treatment of cancer (Table 2) [113].…”

Section: Conclusion Remarks and Perspectivesmentioning

confidence: 99%

The design and development of covalent protein-protein interaction inhibitors for cancer treatment

et al. 2020

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Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the development of drug resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious diseases. Recent improvements in structural biology and chemical reactivity have enabled the design and development of potent and selective covalent PPI inhibitors. In this review, we will highlight the design and development of therapeutic agents targeting PPIs for cancer therapy.

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“…A total of 1 × 10 5 B16‐F10 or HS68 cells were treated with HSCAE groups and UVB treatments or the blank vehicle control for 1 day, respectively . The cells were harvested and lysed with the lysis buffer (Thermo Scientific Pierce RIPA Buffer; 1 mmol L −1 EDTA, 10% (v/v) glycerol, 1% (w/v) Nonidet P‐40, 2 μmol L −1 leupeptin, 50 mmol L −1 Tris–HCl, 137 mmol L −1 sodium chloride, 50 mmol L −1 sodium fluoride, 10 mmol L −1 sodium pyrophosphate, 20 mmol L −1 β ‐glycerophosphate, 1 mmol L −1 phenylmethylsulfonyl fluoride, 0.1 mmol L −1 sodium orthovanadate and 2 μg mL −1 aprotinin; pH 7.5).…”

Section: Methodsmentioning

confidence: 99%

“…The primers used in this experiment were listed in Table S1. wileyonlinelibrary.com/jsfa Western blotting analysis A total of 1 × 10 5 B16-F10 or HS68 cells were treated with HSCAE groups and UVB treatments or the blank vehicle control for 1 day, respectively. 28 The cells were harvested and lysed with the lysis buffer (Thermo Scientific Pierce RIPA Buffer; 1 mmol L −1 EDTA, 10% (v/v) glycerol, 1% (w/v) Nonidet P-40, 2 μmol L −1 leupeptin, 50 mmol L −1 Tris-HCl, 137 mmol L −1 sodium chloride, 50 mmol L −1 sodium fluoride, 10 mmol L −1 sodium pyrophosphate, 20 mmol L −1 -glycerophosphate, 1 mmol L −1 phenylmethylsulfonyl fluoride, 0.1 mmol L −1 sodium orthovanadate and 2 μg mL −1 aprotinin; pH 7.5). Lysates were centrifuged at 13 000×g for 30 min, and the protein quantification in the supernatant was assayed by bicinchoninic acid (BCA) protein assay kit (Sigma-Aldrich Corp.) following centrifugation of lysates at 12 000 rpm for 30 min.…”

Section: Detection Of Mrna Gene Expression Using Qrt-pcr Analysismentioning

confidence: 99%

Reversing UVB‐induced photoaging with Hibiscus sabdariffa calyx aqueous extract

Lin

et al. 2019

J Sci Food Agric

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BACKGROUND Hibiscus sabdariffa is commonly used in daily life and its extract is applied widely in food and cosmetics. However, it has not been evaluated for its anti‐aging effects. RESULTS Hibiscus sabdariffa calyx aqueous extract (HSCAE) has shown potential collagenase activity suppression effects, together with tyrosinase activity inhibition, and anti‐oxidation as a free radical scavenger. The current investigation demonstrated that HSCAE was not cytotoxic in skin fibroblasts, and it significantly decreased ultraviolet B (UVB)‐induced reactive oxygen species (ROS) on a flow cytometry assay. Moreover, HSCAE reduced matrix metalloproteinase (MMP) expression, increased tissue inhibition of metalloproteinase (TIMP)‐1 level, and enhanced collagen content by inhibiting collagenase activity. It also blocked mRNA and protein expressions of melanin production pathway key factors, including the microphthalmia‐associated transcription factor (MITF), tyrosinase, tyrosinase‐related protein‐1 (TRP‐1), and dopachrome tautomerase‐2 (TRP‐2). CONCLUSION These results demonstrated, for the first time, the potential of HSCAE as a natural antioxidant with the ability to maintain collagen production and to decrease melanin syntheses under UVB radiation, for anti‐aging effects. © 2019 Society of Chemical Industry

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Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(iii) metal-based compound

Abstract: This study reports the first use of an iridium(iii) compound and its enantiomer to inhibit the H-Ras/Raf-I PPI in vitro and repress renal cancer xenografts in vivo.

Cited by 117 publications

References 42 publications

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

Lysosome‐targeted potent half‐sandwich iridium(III) α‐diimine antitumor complexes

The design and development of covalent protein-protein interaction inhibitors for cancer treatment

Reversing UVB‐induced photoaging with Hibiscus sabdariffa calyx aqueous extract

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