Discovery of Novel Spiro[3<i>H</i>-indole-3,2′-pyrrolidin]-2(1<i>H</i>)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

Gollner, Andreas; Rudolph, Dorothea; Arnhof, Heribert; Bauer, Markus; Blake, Sophia M.; Boehmelt, Guido; Cockroft, Xiao-Ling; Dahmann, Georg; Ettmayer, Peter; Gerstberger, Thomas; Karolyi‐Oezguer, Jale; Kessler, Dirk; Kofink, Christiane; Ramharter, Juergen; Rinnenthal, Jörg; Savchenko, Alexander; Schnitzer, Renate; Weinstabl, Harald; Weyer-Czernilofsky, Ulrike; Wunberg, Tobias; McConnell, Darryl B.

doi:10.1021/acs.jmedchem.6b00900

Cited by 99 publications

(96 citation statements)

References 70 publications

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“…In this regard, a library of target compounds was energy minimized using MMFF94 force field calculations. The catalytic domain of MDM2 (PDB code 5law) was prepared for docking using OpenEye. OpenEye Omega application was used to generate different conformations of each ligand.…”

Section: Resultsmentioning

confidence: 99%

“…A library of synthesized compounds was energy minimized using the MMFF94 force field, which was followed by the generation of multiconformers using the Omega application. The entire energy‐minimized library was docked with the prepared catalytic domain of MDM2 (PDB code 5 law) using the FRED application to generate a profile of the ligand–receptor complex. The Vida application can be employed as a visualization tool to show the potential binding interactions of the ligands with the receptor of interest.…”

Section: Antiviral Activitymentioning

confidence: 99%

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Discovery of NewS‐Glycosides andN‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis inMCF7 Cells

Khodair

Attia

Gendy

et al. 2019

Journal of Heterocyclic Chem

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Glycosylation of small molecule‐based drugs can dramatically improve the biological activities of the parent scaffold. In the current study, S‐glycosides and N‐glycosides of polyfunctionalized pyridine‐biphenyl system tethered with benzotriazole moiety were designed and synthesized. S‐Glycosides of pyridine‐2‐thione derivatives 5a–h and N‐glycosides of pyridine‐2‐one derivatives 9a,b were synthesized by a facile, convenient, and high‐yielding procedure. The epimers glucose and galactose, acetylated or deacetylated, were used to form the glycone part. The structures of these compounds were confirmed by microanalysis and spectroscopic data (IR, 1H–NMR, and 13C‐NMR). The anticancer activities of the target compounds, in comparison with standard cisplatin, were assessed by MTT assay against MCF7 cell line. Compounds 4f, 4g, 5f, and 5h exhibited the highest cytotoxic effect on MCF7. The anticancer effect of these four compounds induced the apoptosis as evident by the up‐regulated expression of the apoptotic genes Bax and p53 and down‐regulated expression of the anti‐apoptotic gene BCl2. S‐Glycoside derivatives are more active than N‐glycosides. Moreover, the nontoxic doses of the tested compounds were evaluated in MA104, FRHK4, BGM, Hep2, and Vero cells. Compounds 4a–d and 5a–d were also evaluated for their antiviral effect against HSV‐1, HAV, and rotavirus Wa strain. The compounds' results showed less, moderated, and high antiviral activities. The docking study for these compounds with MDM2 revealed that deacetylated galactose is important for binding with the receptor as it facilitates the formation of hydrogen bond in the receptor. Rapid overlay of chemical structures analysis was employed to understand the compounds' similarity on the basis of their shape structure using the Tanimoto scores.

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Section: Resultsmentioning

confidence: 99%

Section: Antiviral Activitymentioning

confidence: 99%

Discovery of NewS‐Glycosides andN‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis inMCF7 Cells

Khodair

Attia

Gendy

et al. 2019

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

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“…Additional spiro‐oxindole MDM2 inhibitors include clinical candidate DS‐3032b and others . The new class of spiro[3 H ‐indole‐3,2′‐pyrrolidin]‐2(1 H )‐ones is not prone to this epimerization . The problem of epimerization was also recently addressed by Aguilar et al.…”

Section: Methodsmentioning

confidence: 99%

“…The X‐ray co‐crystal structure of 1 in MDM2 (PDB ID: https://www.rcsb.org/structure/5LAZ) revealed a hydrogen bond between the basic secondary nitrogen of 1 and the side chain of His96 of the MDM2 protein as being important for the binding of 1 to MDM2 (Scheme C, Figure B) . In contrast many other MDM2–p53 inhibitors address His96 with a carbonyl oxygen functioning as hydrogen bond acceptor .…”

Section: Methodsmentioning

confidence: 99%

Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

et al. 2018

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Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96 MDM2 . The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐ c ]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects.

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“…was optimized to engender small molecular compounds with the inhibitory intensity of nM level on the p53‐MDM2 association . Currently, to more efficiently active function of the wild‐type p53, many efforts have been paid to design and develop potent nonpeptide and low molecular weight inhibitors that competitively occupy the binding cleft of MDM2 to efficiently block the p53‐MDM2 interaction …”

Section: Introductionmentioning

confidence: 99%

Inhibiting mechanism of small molecule toward the p53‐MDM2 interaction: A molecular dynamic exploration

et al. 2018

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Disruption of the p53-MDM2 interaction has been an efficient strategy to renew the function of wild-type p53. In this work, molecular dynamic simulations, molecular mechanics-generalized Born surface area method, and principal component analysis were combined to probe interaction mechanism of inhibitors 2TZ, 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2. The rank of our current predicted binding free energies is in agreement with that of the experimental values. The results demonstrate that the introductions of thiazole and pyridine rings into 2TZ as well as the change in the orientation of inhibitors lead to the increase in the polar interactions of 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2 relative to 2TZ. The information derived from principal component analysis suggests that inhibitor bindings produce significant effect on the binding cleft of MDM2 and make the binding cleft wider and bigger so as to accommodate different type inhibitors. This study is looked forward to contributing theoretical hints for designs of potent inhibitors targeting the p53-MDM2 interaction.

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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

Cited by 99 publications

References 70 publications

Discovery of NewS‐Glycosides andN‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis inMCF7 Cells

Discovery of NewS‐Glycosides andN‐Glycosides of Pyridine‐biphenyl System with Antiviral Activity and Induction of Apoptosis inMCF7 Cells

Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Inhibiting mechanism of small molecule toward the p53‐MDM2 interaction: A molecular dynamic exploration

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