Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53–MDM2 binding inhibitors

Hu, Chunqi; Dou, Xiaoxue; Wu, Yizhe; Zhang, Lei; Hu, Yongzhou

doi:10.1016/j.bmc.2012.01.003

Cited by 13 publications

(4 citation statements)

References 16 publications

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“…The modification of the nitrogen atom by sulfonic derivatives has been carried out [16]. Here, we performed the further modification of imidazoline derivatives at the nitrogen atom using triphosgene and appropriate amines with good yields (Figure 1D, Table 1) [21,22]. To compare both synthetic features and biological activity, we synthesized not only 2,4-dimethoxyphenyl derivatives, but also a number of other alkoxy and halogen derivatives.…”

Section: Chemical Synthesismentioning

confidence: 99%

Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core

et al. 2022

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The use of p53-MDM2 inhibitors is a prospective strategy in anti-cancer therapy for tumors expressing wild type p53 protein. In this study, we have applied a simple approach of two-step synthesis of imidazoline-based alkoxyaryl compounds, which are able to efficiently inhibit p53-MDM2 protein–protein interactions, promote accumulation of p53 and p53-inducible proteins in various cancer cell lines. Compounds 2l and 2k cause significant upregulation of p53 and p53-inducible proteins in five human cancer cell lines, one of which possesses overexpression of MDM2.

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Section: Chemical Synthesismentioning

confidence: 99%

Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core

et al. 2022

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“…Crystal structure analysis revealed that Nutlin interacts with a region in p53, which MDM2 also utilizes to bind with the p53 protein [136]. Other MDM2-specific compounds include RITA [137, 138], HLI98 [139], pyrrolidone derivatives [140], Isoindolinone-based compound [141-143], MITA [144], NSC 333003 [145], a nutlin analog L2 [146], methylbenzo-naphthyridin-5-amine (MBNA) [147], tenovin-6 [148], MI-63 [149], MI-219 [150], pyrrolopyrimidine-based α-helix mimetic [151], etoposide [152], 1,4-diazepines [153], Helical beta-peptide inhibitor [154], thio-benzodiazepines [155], imidazoline derivatives [156, 157], pyrrolidone derivatives, dehydroaltenusin [158], Lissoclinidine B [159], Gambogic acid [160, 161], Chlorofusin [162, 163], Hexylitaconic acid [164, 165], sempervirine [161], Parthenolide [166], berberine [167], Hoiamide D [168] and 25-OCH(3)-PPD [169]. …”

Section: Small Molecules Target the Ubiquitin-proteasome Systemmentioning

confidence: 99%

Targeting the ubiquitin pathway for cancer treatment

Liu

Shaik

Dai

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

111

104

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Proteasome-mediated degradation is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis. In this process, the E3 ubiquitin ligases are responsible for targeting specific substrates (proteins) for ubiquitin-mediated degradation. However, in cancer cells, the stability and the balance between oncoproteins and tumor suppressor proteins are disturbed in part due to deregulated proteasome-mediated degradation. This ultimately leads to either stabilization of oncoprotein(s) or increased degradation of tumor suppressor(s), contributing to tumorigenesis and cancer progression. Therefore, E3 ubiquitin ligases including the SCF types of ubiquitin ligases have recently evolved as promising therapeutic targets for the development of novel anti-cancer drugs. In this review, we highlighted the critical components along the ubiquitin pathway including E1, E2, various E3 enzymes and DUBs that could serve as potential drug targets and also described the available bioactive compounds that target the ubiquitin pathway to control various cancers.

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“…Compound 4 (FP IC 50 = 0.59 µM, MTT HCT116 p53 +/+ IC 50 = 3.73 µM, Figure 2 ) was one of the most potent compounds obtained, although not representing an improvement of potency when compared with nutlin-3a. Nevertheless, these studies helped establishing that changing N 1 side chain interferes mainly with PK properties but also with potency [ 62 , 63 ]. Several other analogs are disclosed in patents from Hoffman-La Roche, presenting the same imidazoline core and other structure variations such as imidazopyridinones [ 30 , 39 , 64 , 65 ].…”

Section: Reactivation Of P53 As a Therapeutic Strategymentioning

confidence: 99%

Chemical Variations on the p53 Reactivation Theme

et al. 2016

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Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the “guardian of the genome”, playing a major role in carcinogenesis. In fact, direct inactivation of the TP53 gene occurs in more than 50% of malignancies, and in tumors that retain wild-type p53 status, its function is usually inactivated by overexpression of negative regulators (e.g., MDM2 and MDMX). Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. In this review, we will present an updated overview of the most relevant small molecules developed to restore p53 function in cancer cells through inhibition of the p53-MDMs interaction, or direct targeting of wild-type p53 or mutated p53. In addition, optimization approaches used for the development of small molecules that have entered clinical trials will be presented.

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Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53–MDM2 binding inhibitors

Cited by 13 publications

References 16 publications

Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core

Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core

Targeting the ubiquitin pathway for cancer treatment

Chemical Variations on the p53 Reactivation Theme

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