Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure–Activity Relationship Study

Rana, Sandeep; Blowers, Elizabeth C.; Tebbe, Calvin; Contreras, Jacob I.; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N.; Arnst, Jamie L.; Munkarah, Adnan; Rattan, Ramandeep; Natarajan, Amarnath

doi:10.1021/acs.jmedchem.6b00400

Cited by 103 publications

(47 citation statements)

References 47 publications

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“…Other than our previously reported research, a number of other research groups has also proven that the α, β-unsaturated ketone functionality, a Michael acceptor is critical for the cancer cell growth inhibition (Rana et al, 2016;Heller et al, 2015). These examples and our previous research exhibited that uniting an α, β-unsaturated ketone in a new synthetic compound can increase the anticancer attributes of a natural product derivatives, and α, the β-unsaturated moiety can be observed as functionality structure to new drug design.…”

Section: Introductionmentioning

confidence: 63%

Discovery of a new tetramethylpyrazine based chalcone with α, β-Unsaturated ketone moiety as a potential anticancer agent

Bukhari

2020

ijrps

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In this study, a new ligustrazine-based chalcone molecule has been synthesized that contains an extra α, β-Unsaturated ketone moiety along with α, the β-Unsaturated carbonyl group of chalone. A new tetramethylpyrazine (TMP) based aldehyde was synthesized to make the TMP (ligustrazine) as part of chalcone and then it was reacted with newly synthesized ketone containing additional α, β-Unsaturated ketone moiety. After characterization, this new compound was evaluated for its effect on different types of cancer cell lines and very promising results were obtained. The growth of these cancer cells was inhibited by newly designed and synthesized compounds, especially for colon and pancreatic cancer cells with IC50 0.04 - 0.05 µM

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Section: Introductionmentioning

confidence: 63%

Discovery of a new tetramethylpyrazine based chalcone with α, β-Unsaturated ketone moiety as a potential anticancer agent

Bukhari

2020

ijrps

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“…18, 34 Nonetheless, the non-disulfide, nucleophilic cysteines, Cys38 and Cys120, located at the p65 DNA-binding interface constitute unique structural features of p65 that lends itself towards the development of covalent chemical modulators. Furthermore, previous studies from other groups have demonstrated covalent engagement of p65 Cys38 with diverse small molecules, 6, 37–41 as well as covalent targeting of p65 Cys120. 42 …”

Section: Introductionmentioning

confidence: 85%

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

et al. 2016

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The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant towards small molecule inhibition despite the substantial number of compounds known to inhibit upstream proteins in the activation pathway. Given the roles of many of these upstream proteins in multiple biochemical pathways, targeting the p50/p65 heterodimer offers an opportunity for enhanced on-target specificity. Towards this end, the p65 protein presents two non-disulfide cysteines, Cys38 and Cys120, at its DNA-binding interface that are amenable to targeting by covalent molecules. The natural product helenalin, a sesquiterpene lactone, has been previously shown to target Cys38 on p65 and ablate its DNA-binding ability. Using helenalin as inspiration, simplified helenalin analogues were designed, synthesized, and shown to inhibit induced canonical NF-κB signaling in cell culture. Moreover, two simplified helenalin probes were proficient at forming covalent protein adducts, binding to Cys38 on recombinant p65, and targeting p65 in HeLa cells without engaging canonical NF-κB signaling proteins IκBα, p50, and IKKα/β. These studies further support that targeting the p65 transcription factor-DNA interface with covalent small molecule inhibitors is a viable approach towards regulating canonical NF-κB signaling.

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“…Recently, by means of molecular docking followed by in cellulo screening we uncovered that Isatin Schiff and Mannich based derivatives (ISMBDs) were able to activate p53 [42]. 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].…”

Section: Introductionmentioning

confidence: 93%

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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Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure–Activity Relationship Study

Cited by 103 publications

References 47 publications

Discovery of a new tetramethylpyrazine based chalcone with α, β-Unsaturated ketone moiety as a potential anticancer agent

Discovery of a new tetramethylpyrazine based chalcone with α, β-Unsaturated ketone moiety as a potential anticancer agent

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

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

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