Chemistry of Indoles Carrying a Basic Function, Part 31 Synthesis of Spiro[cyclopropane‐1,3′[3H]indol]‐2′(1′H)‐ones with Antihypoxic Effects

Moldvai, István; Gács‐Baitz, Eszter; Balázs, Mihály; Incze, Mária; Szántay, Csaba

doi:10.1002/ardp.19963291206

Cited by 11 publications

(6 citation statements)

References 8 publications

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“…Treatment of indazol-6-ylmethyleneindolin-2-one ( 7 ) with trimethylsulfoxonium iodide under modified Corey–Chaykovsky , conditions gave the racemic cyclopropyl analogues in a 14:1 mixture of trans ( 8 ) and cis ( 9 ) diastereomers, as shown in Scheme , which were separated by silica gel chromatography. The trans relative stereochemistry was defined based on the work by Moldvai and co-workers as described for a series of pyridyl spirocyclopropylindolones . Irradiation of the 2-H cyclopropane proton resonance only showed a NOE enhancement to one of the 3-H cyclopropane protons of 8 .…”

Section: Results and Discussionmentioning

confidence: 99%

The Discovery of Polo-Like Kinase 4 Inhibitors: Design and Optimization of Spiro[cyclopropane-1,3′[3H]indol]-2′(1′H)-ones as Orally Bioavailable Antitumor Agents

Sampson¹,

Liu²,

Patel³

et al. 2014

J. Med. Chem.

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Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

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Section: Results and Discussionmentioning

confidence: 99%

The Discovery of Polo-Like Kinase 4 Inhibitors: Design and Optimization of Spiro[cyclopropane-1,3′[3H]indol]-2′(1′H)-ones as Orally Bioavailable Antitumor Agents

Sampson¹,

Liu²,

Patel³

et al. 2014

J. Med. Chem.

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“…They are classical one‐carbon synthon and have been utilised in many transformations. [ 17 ] Moldavai et al, used modified Corey–Chaykovsky conditions for the cyclopropanation of 3‐alkenyl oxindoles 7 where sulfur ylide was generated in situ from TMSOI and NaH (Scheme 5). [ 17a ] Recently, Sampson et al, also disclosed the same method to synthesize CFI‐400945 (2), a PLK‐4 inhibitor and now it is under clinical trials for the treatment of breast cancer.…”

Section: Synthesis Of Spirocyclopropyl Oxindolesmentioning

confidence: 99%

Syntheses and Applications of Spirocyclopropyl Oxindoles: A Decade Review

2020

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Spirocyclopropyl oxindole represents an emerging framework by unique amalgamation of versatile 2‐oxindole motif and highly strained cyclopropane unit. This scaffold is remarkable for its diverse medicinal and synthetic applications. The present review delivers a comprehensive overview of the strategies to afford spirocyclopropyl oxindoles and their potential synthetic transformations. The syntheses of spirocyclopropyl oxindoles have been described based on the type of precursors, including isatin, 3‐alkenyl oxindole, diazooxindole, oxindole, and 3‐chlorooxindole. Besides, the utility of different cyclopropanation reagents like sulfur ylide, MBH‐carbonate, carbenoid, vinyl selenone, etc. have also been emphasized. Furthermore, various ring‐expansion/opening reactions of spirocyclopropane oxindoles using dipolarophiles/nucleophiles have critically been illustrated.

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“…recently [28], the Simmons-Smith reaction [29,30], reaction with dimethyloxosulfonium methylide [31], and cyclopropanation with diazomethane [32] in the presence of a catalyst are frequently used.…”

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confidence: 99%