Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction.

@article{Gollner2016DiscoveryON,
  title={Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction.},
  author={Andreas Gollner and Dorothea Rudolph and Heribert Arnhof and Markus J. Bauer and Sophia M. Blake and Guido Boehmelt and Xiao-Ling Cockroft and Georg Dahmann and Peter Ettmayer and Thomas Gerstberger and Jale Karolyi-Oezguer and Dirk Kessler and Christiane Kofink and Juergen Ramharter and J{\"o}rg Rinnenthal and Alexander Savchenko and Renate Schnitzer and Harald Weinstabl and Ulrike Weyer-Czernilofsky and Tobias Wunberg and Darryl B. McConnell},
  journal={Journal of medicinal chemistry},
  year={2016},
  volume={59 22},
  pages={
          10147-10162
        }
}
Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein… Expand
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References

SHOWING 1-10 OF 64 REFERENCES
Identification of the spiro(oxindole-3,3'-thiazolidine)-based derivatives as potential p53 activity modulators.
TLDR
The design of new analogues of spirooxoindolepyrrolidine nucleus as modulators of p53 activity are reported, inhibiting cell growth of different human tumor cells at submicromolar and micromolar concentrations. Expand
Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2'-thiazolidine]-based p53 modulators.
TLDR
Derivative 5-bromo-3'-(cyclohexane carbonyl)-1-methyl-2-oxospiro[indoline-3,2'-thiazolidine] (4n) emerged as the most potent compound, inhibiting in vitro 30% of p53-MDM2 interaction at 5 μM and the cell growth of different human tumor cells at nanomolar concentrations. Expand
Benzimidazole-2-one: a novel anchoring principle for antagonizing p53-Mdm2.
TLDR
It is concluded that the 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide scaffold might be a good starting point to further optimize the affinities to Mdm2. Expand
Spiro-oxindole derivative 5-chloro-4',5'-diphenyl-3'-(4-(2-(piperidin-1-yl) ethoxy) benzoyl) spiro[indoline-3,2'-pyrrolidin]-2-one triggers apoptosis in breast cancer cells via restoration of p53 function.
TLDR
G613 represents a potent small-molecule inhibitor of the Mdm2-p53 interaction and can serve as a promising lead for developing a new class of anti-cancer therapy for breast cancer patients. Expand
Efficient synthesis of novel antiproliferative steroidal spirooxindoles via the [3+2] cycloaddition reactions of azomethine ylides
TLDR
A series of novel steroidal spirooxindoles 3a-h were synthesized from pregnenolone in a high regioselective manner using the 1,3-dipolar cycloaddition as the key step and exhibited moderate to good antiproliferative activity against the tested cell lines. Expand
Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles
TLDR
This study has designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution, which undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Expand
Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition
Spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrid compounds were obtained in excellent yields from the regio- and stereoselective reaction between β-nitrostyrenes and non-stabilizedExpand
Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction
TLDR
Two series of 2,5-diketopiperazines are designed and synthesised as inhibitors of the MDM2-p53 interaction and shown the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay. Expand
1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR.
TLDR
A library of 1,4-benzodiazepine-2,5-diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor, a miniaturized thermal denaturation assay, leading to sub-micromolar antagonists of the p 53-HDM2 interaction. Expand
1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity
TLDR
1,4‐Thienodiazepine‐2,5‐diones have been synthesized via the Ugi‐Deprotection‐Cyclization (UDC) approach starting from Gewald 2‐aminothiophenes in a convergent and versatile manner and some compounds exhibited promising antagonistic activity. Expand
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