Synthesis of Pyrazolyl‐Pyrazoles and Pyrazolyl‐[1,2,4]‐Triazolo[3,4‐<i>d</i>][1,5]Benzothiazepines as p53 Activators Using Hydrazonoyl Chlorides

Gomha, Sobhi M.; Farghaly, Thoraya A.; Sayed, Abdelwahed R.; Abdalla, Mohamed M.

doi:10.1002/jhet.2455

Cited by 11 publications

(5 citation statements)

References 47 publications

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“…Some people even use the method of activating p53 to develop anticancer drugs. [68] But so far, there are still no drugs on the market for p53-MDM2. However, with the advancement of technology and the continuous progress of trials, we have reason to believe that p53-MDM2/MDMx inhibitors will be used in the first-line clinical treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis and Mechanism of p53‐MDM2 Inhibitors with Heterocyclic Structures: A Focused Review

Ji,

Zhang,

Zhang

et al. 2023

ChemistrySelect

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P53 gene mutation is one of the important causes in tumors. p53‐MDM2 (murine double minute 2) inhibitors can interrupt p53‐dependent gene transcription activity, and inhibit p53‐mediated apoptosis, block p53‐MDM2/MDMx interaction, and significantly reduce DNA formation. In this article, we focused on the synthesis methods about nutlins and other p53 small molecule inhibitors, in order to find potential new structure for novel p53 small molecule inhibitor synthesizing.

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Section: Discussionmentioning

confidence: 99%

“…A small amount of p53‐MDM2 with other parent structures inhibitors have also entered clinical studies. Some people even use the method of activating p53 to develop anticancer drugs [68] . But so far, there are still no drugs on the market for p53‐MDM2.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Mechanism of p53‐MDM2 Inhibitors with Heterocyclic Structures: A Focused Review

Ji,

Zhang,

Zhang

et al. 2023

ChemistrySelect

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“…In continuation to our previous studies 44 – 46 , 49 – 51 , we set our design strategy to synthesize new series of spirooxindole-based p53 activators via pharmacophoric hybridization approach. Herein, we utilized the spiro[3 H -indole-3,2′-pyrrolidin]-2(1 H )-one scaffold as promising chemically stable core for installing a pyrazole motif via a carbonyl spacer inspired by the potent lead pyrazole-based p53 activators 55 – 58 (Fig. 2 ).…”

Section: Design Rationalementioning

confidence: 99%

Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells

Islam

Al‐Majid

Sholkamy

et al. 2023

Sci Rep

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Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC50 = 10.3 µM) and HepG2 (IC50 = 18.6 µM), 8m against A549 (IC50 = 17.7 µM), and 8k against MDA-MB-453 (IC50 = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC50 by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.

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“…Also, there is a rapid evolution of drug-resistant pathogens that raise the need for the discovery of new drugs to counterbalance the effects of this resistance. Pyrazolines have been found to possess diverse biological activities such as anticancer [ 2 , 3 , 4 ], antitumor [ 5 ], antioxidant [ 6 ], antimicrobial [ 7 , 8 ], antitubercular [ 9 ], antimalarial [ 10 ], anti-amoebic [ 11 ], DPPH radical scavenging, anti-diabetic [ 12 ], antiviral [ 13 ] and amine oxidase [ 14 ]. Also, thiazoles are known to have anticonvulsant [ 15 ], antimicrobial [ 16 ], anti-inflammatory [ 17 ], anticancer [ 18 , 19 , 20 ], antidiabetic [ 21 ], anti-HIV [ 22 ], anti-Alzheimer [ 23 ], antihypertensive [ 24 ], antifungal [ 25 ], and antioxidant [ 26 ] activities.…”

Section: Introductionmentioning

confidence: 99%

Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents

et al. 2018

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The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using the solvent-drop grinding method. The structure of the synthesized compounds was elucidated using elemental and spectroscopic analyses (IR, NMR, and Mass). The activity of these compounds against human hepatocellular carcinoma cell line (HepG2) was tested and the results showed that the pyrazoline 11f, which has a fluorine substituent, is the most active. The antimicrobial activities of the newly synthesized compounds were determined against two fungi and four bacterial strains, and the results indicated that some of the newly synthesized pyrazolines are more potent than the standard drugs against test organisms.

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Synthesis of Pyrazolyl‐Pyrazoles and Pyrazolyl‐[1,2,4]‐Triazolo[3,4‐d][1,5]Benzothiazepines as p53 Activators Using Hydrazonoyl Chlorides

Cited by 11 publications

References 47 publications

Synthesis and Mechanism of p53‐MDM2 Inhibitors with Heterocyclic Structures: A Focused Review

Synthesis and Mechanism of p53‐MDM2 Inhibitors with Heterocyclic Structures: A Focused Review

Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells

Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents

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