2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents

Wei, Xinwei; Yuan, Jing-Mei; Huang, Wentao; Chen, Nan-Ying; Li, Xiaojuan; Pan, Cheng-Xue; Mo, Dong‐Liang; Su, Gui‐Fa

doi:10.1016/j.ejmech.2019.111851

Cited by 30 publications

(13 citation statements)

References 34 publications

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“…Researchers have shown that phosphorylation of P53 (Ser15, Ser20, Ser37, Ser46) modulates its activation to induce apoptosis through multiple effectors, 28 , 29 and it then upregulates the levels of the pro-apoptosis protein Bax whereas it downregulates the anti-apoptosis protein Bcl-2, activating caspase-9 and caspase-3 to induce apoptosis. 30 This P53-dependent apoptosis pathway contributes to vascular cells developing antiapoptotic and proliferative phenotypes, leading to intimal and medial thickening. 31 Meanwhile, P53 is one of the target genes of miR-30a involved in mitochondrial impairment and myocardial apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension

Qiu

Bai

et al. 2021

Molecular Therapy - Nucleic Acids

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The excessive and ectopic pulmonary artery smooth muscle cells (PASMCs) are crucial to the pathogenesis of pulmonary arteriole (PA) remodeling in pulmonary arterial hypertension (PAH). We previously found that microRNA (miR)-30a was significantly increased in acute myocardial infarction (AMI) patients and animals, as well as in cultured cardiomyocytes after hypoxia, suggesting that it might be strongly associated with hypoxia-related diseases. Here, we investigated the role of miR-30a in the PASMC remodeling of PAH. The expression of miR-30a was higher in the serum of PAH patients compared with healthy controls. miR-30a was mainly expressed in PAs and was increased in PASMCs after hypoxia, mediating the downregulation of p53 tumor suppressor protein (P53). Genetic knockout of miR-30a effectively decreased right ventricular (RV) systolic pressure (RVSP), PA, and RV remodeling in the Su5416/hypoxia-induced and monocrotaline (MCT)-induced PAH animals. Additionally, pharmacological inhibition of miR-30a via intratracheal liquid instillation (IT-L) delivery strategy showed high efficiency, which downregulated miR-30a to mitigate disease phenotype in the Su5416/hypoxiainduced PAH animals, and these beneficial effects could be partially reduced by simultaneous P53 inhibition. We demonstrate that inhibition of miR-30a could ameliorate experimental PAH through the miR-30a/P53 signaling pathway, and the IT-L delivery strategy shows good therapeutic outcomes, providing a novel and promising approach for the treatment of PAH.

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Section: Discussionmentioning

confidence: 99%

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension

Qiu

Bai

et al. 2021

Molecular Therapy - Nucleic Acids

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“…Thus, PK083 binds to the mutant form p53Y220C and restores its transcriptional activity, causing apoptosis [ 36 , 80 , 81 ]. Analogs of quinazoline (2-styryl-4-aminoquiazoline, CP-31398) [ 82 , 83 , 84 ] reactivate p53. Alkylating agents are involved in the restoration of the structure of the p53 protein by directly binding to and modifying its mutant forms [ 85 ].…”

Section: Ways To Overcome Radioresistance Upon Modulation Of P53-family Proteinsmentioning

confidence: 99%

The p53 Protein Family in the Response of Tumor Cells to Ionizing Radiation: Problem Development

et al. 2021

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Survival mechanisms are activated in tumor cells in response to therapeutic ionizing radiation. This reduces a treatments effectiveness. The p53, p63, and p73 proteins belonging to the family of proteins that regulate the numerous pathways of intracellular signal transduction play a key role in the development of radioresistance. This review analyzes the p53-dependent and p53-independent mechanisms involved in overcoming the resistance of tumor cells to radiation exposure.

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“…An increase in quenching of EB‐CTDNA fluorescence upon addition of 4b to the EB‐CTDNA complex suggests intercalation of 4b with CT‐DNA. Gel electrophoresis was also performed to confirm intercalation where the movement of pBR322 plasmid DNA was reduced upon the addition of 4b confirming intercalation (Wei et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

DNA intercalators as anticancer agents

et al. 2022

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Cancer is one of the most prevailing disease conditions, which occurs due to uncontrolled cell division either due to natural mutation to the genes or due to changes induced by physical, chemical, or biological carcinogens. According to WHO, it is the second leading cause of death worldwide and has reported 10 million deaths in 2020. Hence, there arises the need for better chemotherapies and DNA intercalators are one such emerging therapy for cancer. DNA intercalating agents reversibly intercalate with the double‐helical structure of DNA by interacting with adjacent base pairs and disrupting the structure of DNA and thereby causing cell death. Here, we discuss the different classes of organo‐intercalators used in cancer therapy describing their anticancer and intercalation ability by different methods along with their structure–activity relationship and mechanism of action.

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2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents

Cited by 30 publications

References 34 publications

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension

The p53 Protein Family in the Response of Tumor Cells to Ionizing Radiation: Problem Development

DNA intercalators as anticancer agents

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