Synthesis, Cytotoxicity, DNA Binding and Apoptosis of  Rhein-Phosphonate Derivatives as Antitumor Agents

Ye, Man-Yi; Yao, Guiyang; Wei, Jingchen; Pan, Ying‐Ming; Liao, Zhi‐Xin; Wang, Hengshan

doi:10.3390/ijms14059424

Cited by 19 publications

(7 citation statements)

References 55 publications

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“…Many organophosphorus derivatives exhibited a broad range of biological activities such as antidepressant, antibiotic, and cytotoxic. 7,8 In view of the above observations and as a continuation of our previous work on the synthesis of new structural analogs of alkaloids isolated from P. harmala seeds, 9 we report here the synthesis of new series of α-amino acid ester and phosphonate derivatives of (±)-vasicinone. Furthermore, the new synthesized compounds were tested in vitro for their acetylcholinesterase (AChE) and 5-lipoxygenase (5-LOX) inhibitor potentials and cytotoxic activity against MCF-7 (Human breast carcinoma), OVCAR-3 (human ovarian carcinoma), and HCT-116 (Human colon carcinoma).…”

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confidence: 82%

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New Bioactive Esters and Phosphonates Semisynthesized From (±)-Vasicinone: An Alkaloid Isolated From Peganum harmala

Filali

Jelassi

Jannet

2019

Natural Product Communications

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A series of N-tosyl α-amino acids 2a-e, prepared using a tosyl chloride protecting group, was condensed with (±)-vasicinone 1, isolated from the seeds of the plant Peganum harmala, to generate the corresponding esters 3a-e and 3b′-e′. (±)-Vasicinone 1 was also reacted with chloroacetic acid chloride to afford a new chlorinated ester 4 which was refluxed with trialkyl phosphites to give 2 new phosphonates 5a,b. All synthesized compounds were characterized with the help of spectroscopic means, including NMR (1H, 13C, and 31P) and ES-HRMS, and then screened for their in vitro anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), and cytotoxic activities (MCF-7, OVCAR-3, and HCT-116 cell lines). Most synthesized derivatives exhibited a cytotoxic activity against 3 cell lines used. The phosphonate derivative 5b was found to be the most active one (IC50 = 63.7 ± 1.4 µM) against AChE enzyme. Only 2 diastereoisomers 3e and 3e′ exhibited activity against 5-LOX enzyme with IC50 values of 63.1 ± 4.2 and 79.2 ± 8.3 µM, respectively.

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confidence: 82%

“…Many organophosphorus derivatives exhibited a broad range of biological activities such as antidepressant, antibiotic, and cytotoxic. 7,8…”

mentioning

confidence: 99%

New Bioactive Esters and Phosphonates Semisynthesized From (±)-Vasicinone: An Alkaloid Isolated From Peganum harmala

Filali

Jelassi

Jannet

2019

Natural Product Communications

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“…Apoptosis, a physiological process for eliminating malignant cells including cancer cells, plays a key role in anticancer without damaging normal cells and tissues 3, 4. Previously, the substantial evidence showed that Rhein induces the cell cycle S-phase arrest and results in DNA fragmentation via complex mechanisms including decreasing Bcl-2 and cleaved caspase-3 level and increasing ROS and phosphorylated c-JNK level 2, 5, 6. These results suggest that Rhein induces apoptosis in various human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Rhein induces liver cancer cells apoptosis via activating ROS-dependent JNK/Jun/caspase-3 signaling pathway

et al. 2020

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Background: Liver cancer is one of the leading cancers in China. Rhein induces apoptosis in various human cancer cells, but the underlying mechanism is still unknown.Methods: In the present study, the MTT assay was used to detect the anti-cell growth ability of Rhein on liver cancer cells. Hoechst33342 staining and FACS assay were used to detect cell apoptosis. Finally, the effect of Rhein on JNK protein' phosphorylation level and the apoptosis-associated proteins were determined by western blot.Results: Here, we found that Rhein significantly inhibited the cell viability in a dose-dependent and time-dependent manner both in HepG2 and Huh7 cells. Also, Rhein increased the apoptosis, mitochondrial membrane potential (MMP) and cell-cycle arrest. Furthermore, we observed that the ROS level and JNK/Jun/caspase-3 signaling pathway played a key role in Rhein induced apoptosis. Our study further demonstrated that Rhein increases apoptosis by inducing the generation of ROS and activating the JNK/Jun/caspase-3 signaling pathway.Conclusions: The present study showed that Rhein promotes apoptosis via regulating ROS/JNK/Jun/caspase-3 signaling pathway both in HepG2 and Huh7 cells. Rhein may be a promising therapeutic candidate for the treatment of liver cancer.

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“…In general, most DNA binding compounds containing a linear or angular planar chromophore with apolyaromatic ring can influence the structures and physiological functions of DNA [11]. To enhance antitumor activity, generally the DNA binding compounds should carry one or two flexible basic side chains on chromophore [12]. The flexible basic side chains are highly influential in directing the thermodynamic-binding mechanism, geometry of the ligand-DNA complex and sequence selectivities [13].…”

Section: Introductionmentioning

confidence: 99%

Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation

Wang

et al. 2015

Molecules

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A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti-and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic OPEN ACCESSMolecules 2015, 20 14792 effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.

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Synthesis, Cytotoxicity, DNA Binding and Apoptosis of Rhein-Phosphonate Derivatives as Antitumor Agents

Cited by 19 publications

References 55 publications

New Bioactive Esters and Phosphonates Semisynthesized From (±)-Vasicinone: An Alkaloid Isolated From Peganum harmala

New Bioactive Esters and Phosphonates Semisynthesized From (±)-Vasicinone: An Alkaloid Isolated From Peganum harmala

Rhein induces liver cancer cells apoptosis via activating ROS-dependent JNK/Jun/caspase-3 signaling pathway

Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation

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