Synthesis, in Vitro, and in Cell Studies of a New Series of [Indoline-3,2′-thiazolidine]-Based p53 Modulators

Bertamino, Alessia; Soprano, Maria; Musella, Simona; Rusciano, Maria Rosaria; Sala, Marina; Vernieri, Ermelinda; Sarno, Veronica Di; Limatola, Antonio; Carotenuto, Alfonso; Cosconati, Sandro; Grieco, Paolo; Novellino, Ettore; Illario, Maddalena; Campiglia, Pietro; Gómez-Monterrey, Isabel

doi:10.1021/jm400311n

Cited by 70 publications

(47 citation statements)

References 49 publications

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“…The same group also developed a series of diastereomeric spiro-oxindoles such as MI888 which is a potent MDM2 inhibitor (Ki =0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy [366]. Simultaneously, other drugs that have been reported so far include pyrazole and imidazole compounds [367], imidazole-indoles [368], isoindolinones [369] pyrrolidinones such as PXN822 [370,371], piperidines [372], spirooxindoles [373] and the sulphonamide NSC279287 [374]. …”

Section: Small Molecule Activators Of P53 Pathwaymentioning

confidence: 99%

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

et al. 2014

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Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism.

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Section: Small Molecule Activators Of P53 Pathwaymentioning

confidence: 99%

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

et al. 2014

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“…5-Bromo-3 0 -(cyclohexane carbonyl)-1-methyl-2-oxospiro[indoline-3,2 0 -thiazolidine] (10) is the most potent compound in this series, inhibiting, in vitro, 30% of p53-MDM2 interaction and the cell growth of different human tumor cells at nanomolar concentrations [112] (Fig. 8).…”

Section: Spiro-thiazolidine-based Inhibitorsmentioning

confidence: 99%

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

et al. 2016

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As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship.

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“…The 3‐thiazolidine scaffold represents an important heterocyclic structural motif in both medicinal chemistry and agrochemistry . Furthermore, this heterocycle is widely present in natural products and is a key structure in penicillins as presumably most prominent example.…”

Section: Introductionmentioning

confidence: 99%

Biocatalytic Reduction of 2‐Monosubstituted 3‐Thiazolines Using Imine Reductases

Zumbrägel

Wagner

Weißing

et al. 2019

Journal of Heterocyclic Chem

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The application of a straightforward biocatalytic technology for the reduction of racemic 2‐monosubstituted 3‐thiazolines, which are easily prepared via Asinger‐multicomponent reaction, is reported. The biocatalytic reduction yields racemic 2‐monosubstituted 3‐thiazolidines, which are difficult to be prepared by means of classic chemical routes, in moderate to high yields. Moreover, our study clarifies the stereochemical reaction course of the biocatalytic reduction. Furthermore, the efficiency of this biocatalytic technology is demonstrated in an experiment at an elevated substrate concentration of 60 mM leading to 96% conversion.

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Synthesis, in Vitro, and in Cell Studies of a New Series of [Indoline-3,2′-thiazolidine]-Based p53 Modulators

Cited by 70 publications

References 49 publications

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Biocatalytic Reduction of 2‐Monosubstituted 3‐Thiazolines Using Imine Reductases

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