Isatin derivatives with activity against apoptosis-resistant cancer cells

Evdokimov, Nikolai M.; Magedov, I. V.; McBrayer, Dominic; Kornienko, Alexander

doi:10.1016/j.bmcl.2016.02.015

Cited by 46 publications

(25 citation statements)

References 30 publications

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“…In line with this, Rana and colleagues have shown that isatin-derived spirocyclic a-methylene-g-butyrolactone can be used as a novel anticancer agent [43]. Furthermore, a series of isatin-based heterocyclic compounds were found to inhibit proliferation of cancer cell lines resistant to apoptosis [44]. In the current study, we elucidated the molecular mechanism of their function and demonstrated that these small molecule activators of p53 operated via blunting the interaction between p53 and Mdm2.…”

Section: Introductionsupporting

confidence: 62%

Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis

et al. 2018

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The p53 protein is a key tumor suppressor in mammals. In response to various forms of genotoxic stress p53 stimulates expression of genes whose products induce cell cycle arrest and/or apoptosis. An E3-ubiquitin ligase, Mdm2 (mouse-double-minute 2) and its human ortholog Hdm2, physically interact with the amino-terminus of p53 to mediate its ubiquitin-mediated degradation via the proteasome. Thus, pharmacological inhibition of the p53-Mdm2 interaction leads to overall stabilization of p53 and stimulation of its anti-tumorigenic activity. In this study we characterize the biological effects of a novel class of non-genotoxic isatin Schiff and Mannich base derivatives (ISMBDs) that stabilize p53 on the protein level. The likely mechanism behind their positive effect on p53 is mediated via the competitive interaction with Mdm2. Importantly, unlike Nutlin, these compounds selectively promoted p53-mediated cell death. These novel pharmacological activators of p53 can serve as valuable molecular tools for probing p53-positive tumors and set up the stage for development of new anti-cancer drugs.

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Section: Introductionsupporting

confidence: 62%

Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis

et al. 2018

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“…The anticancer SAR of compounds 18 (IC 50 : 3.2 to >100 μM, MTT assay) and 19 (IC 50 : 3.9–44.6 μM) against apoptosis‐resistant U373 glioblastoma, A549 non‐small‐cell lung cancer, SKMEL‐28 melanoma, OE21 esophageal cancer along with apoptosis sensitive cells, including HS683 glioma, B16F10 murine melanoma, MCF‐7 breast cancer, and PC‐3 prostate cancer revealed that introduction of halogen atoms into the C‐7 position of isatin moiety could not improve the activity apparently. [ 58 ] The oxime at the C‐3 position was favorable to the activity, and compounds with oxime were more potent than the corresponding ketone analogs. Compound 19d (IC 50 : 3.9–13.9 μM) was active against all tested apoptosis‐resistant and sensitive cancer cell lines, but the activity was far lower than that of the reference β‐lapachone (IC 50 : <0.01–0.8 μM).…”

Section: Anticancer Activitymentioning

confidence: 99%

Isatin dimers and their biological activities

Zhang

Liu

et al. 2020

Archiv der Pharmazie

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Dimerization is a promising strategy to develop novel drug candidates that could extend the biological spectrum, enhance the activity, overcome drug resistance, as well as improve pharmacological, pharmacokinetic, and physicochemical profiles. Isatin dimers possess a broad spectrum of biological properties and the isatin dimer indirubin has already been used in the clinic, revealing the potential of isatin dimers as putative drugs. This review covers the recent advances of isatin dimers as pharmacologically significant scaffolds and the structure–activity relationship to set up the direction for the design and development of isatin dimers with higher efficiency and lower toxicity.

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“…The biological data used in this study was the anti-cancer activity against MCF7, (in terms of -log IC 50 ), of a set of 109 isatin derivatives [43][44][45][46][47][48][49][50][51]. The data set was classified into calibration and prediction set by kenardston algorithm of the 20 prediction molecules from the spaces of the calculated descriptors.…”

Section: Data Setmentioning

confidence: 99%

QSAR and Docking Study of Isatin Analogues as Cytotoxic Agents

Sabet

Khabnadideh

Fathi

et al. 2019

JPRI

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Computational chemistry is a unique method in the drug discovery process?? Explain Why?. In this study 109 molecules containing the isatin backbone were subjected to quantitative structure-activity relationship analysis to find the structure requirements for ligand binding. The structures were sketched and optimized in Hyperchem. The structural invariants used in this study were those obtained from whole molecular structures: by both hyperchem and dragon software (16 types of descriptors). Four chemometrics methods including MLR, FA-MLR, PCR and GA-PLS were employed to make connections between structural parameters and anticancer effects. MLR models revealed the effects of constitutional, functional, geometrical, WHIM and GETAWAY descriptors having higher impact on anticancer activity of the compounds. GA-PLS showed functional, constitutional and chemical descriptor indices to be the most significant parameters on anticancer activity. Moreover, the result of FA-MLR analysis revealed the effects of functional descriptors on the anticancer activity. A comparison between the different statistical methods employed and the results indicated that GA-PLS represented superior results and could explain and predict 81% and JPRI, 27(5): 1-22, 2019; Article no.JPRI.48076 2 78% variances in the PIC 50 data, respectively. Docking studies of these compounds were also investigated and promising results were obtained showing that some compounds were introduced as a good candidate for cancer agents. Original Research Article

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Isatin derivatives with activity against apoptosis-resistant cancer cells

Cited by 46 publications

References 30 publications

Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis

Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis

Isatin dimers and their biological activities

QSAR and Docking Study of Isatin Analogues as Cytotoxic Agents

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