Advanced palladium free approach to the synthesis of substituted alkene oxindoles <i>via</i> aluminum-promoted Knoevenagel reaction

Novikova, Daria; Grigoreva, Tatyana A.; Zolotarev, Andrey A.; Гарабаджиу, А. В.; Трибулович, В. Г.

doi:10.1039/c8ra07576j

Cited by 14 publications

(16 citation statements)

References 37 publications

(29 reference statements)

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“…However, we developed a method of condensation, which allows to obtain benzophenone derivatives according to the same scheme. [37] Therefore, we synthesized several new compounds between 3 a and C24 with intermediate activity according to Scheme 1. The lipophilicity of molecule binding fragments was the main varying parameter when changing the structure from 3 a to C24 ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

et al. 2020

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AMP‐activated protein kinase (AMPK) is currently the subject of intensive study and active discussions. AMPK performs its functions both at the cellular level, providing the switch between energy‐consuming and energy‐producing processes, and at the whole body level, particularly, regulating certain aspects of higher nervous activity and behavior. Control of such a ‘main switch’ compensates dysfunctions and associated diseases. In the present paper, we studied the binding of 3‐benzylidene oxindoles to the kinase domain of the AMPK α‐subunit, which is thought to prevent its interaction with the autoinhibitory domain and thus result in the AMPK activation. For this purpose, we developed the cellular test system based on the AMPKAR plasmid, which implements the FRET effect, synthesized a number of 3‐benzylidene oxindole compounds and simulated their binding to various sites of the kinase domain. The most probable binding site for the studied compounds was established by the correlation of calculated and experimental data. The obtained results allow to analyze various classes of AMPK activators using virtual and high‐content screening.

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Section: Resultsmentioning

confidence: 99%

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

et al. 2020

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“…The library was based on classes of compounds studied in our laboratory, which in in vitro experiments showed activity comparable to the activity of substances at the stage of clinical trials [18,19] (Fig. 1).…”

Section: Metarials and Methodsmentioning

confidence: 99%

“…1). In the course of work on optimization of MDM2 inhibitors based on indolinones and isoindolinones [19][20][21], we found fragments of the structure that can be modified with minimal risk of a decrease in the target activity, i.e. ability to inhibit the formation of the complex MDM2-p53.…”

Section: Metarials and Methodsmentioning

confidence: 99%

Treatment of chemoresistant cell lines with indolinone-based small molecules

et al. 2020

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Reduced delivery of the drug into the cell due to increased activity of specific transporter P-glycoprotein is one of the main mechanisms of drug resistance development. The inhibition of the activity of such a pump increases the intracellular concentration of the drug and contributes to cancer cell death. The combination of factors that allows one to overcome genetically determined resistance and to trigger apoptosis in one small molecule compound can lead to the development of new type of drugs for personalized therapy of chemoresistant tumors. In the course of work on optimization of MDM2 inhibitors based on indolinones and isoindolinones, we found fragments of the structure that can be modified with minimal risk of a decrease in the target activity. The combination of in silico and in vitro methods allowed the selection of compounds that showed strong binding to the target sites of P-glycoprotein and MDM2, and a good combination of solubility - membrane-active properties, which implies high bioavailability of the drug.

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“…Recently, Novikova et al reported a palladium-free approach to the synthesis of YLF466D via aluminum-promoted Knoevenagel reaction. 21 However, the E-and Z-isomers (10 and 11) produced by this method have E/Z ≈ 37/63 (Eisomer is required due to its higher activity toward AMPK) and the separation of these isomers would be challenging.…”

Section: Palladium-catalyzed C−h Activation (Key Intermediate 7)mentioning

confidence: 99%

“…Recently, YLF466D was reported to be prepared through a Lewis acid-promoted Knoevenagel reaction, which gave a mixture of Z-and E-isomers, which was subsequently separated via column chromatography. 21 As the Z-isomer displayed lower activating efficacy toward AMPK, 20 this geometryunselective approach to YLF466D is not an ideal choice for its scale-up synthesis.…”

Section: ■ Introductionmentioning

confidence: 99%

Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator

Yin¹,

Zhan²,

et al. 2021

Org. Process Res. Dev.

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Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of YLF466D in kilogram scale. The process features a palladium-catalyzed C−H activation under mild reaction conditions, geometry selectivity, effective impurities purging, and low levels of residual solvents in the final active pharmaceutical ingredient (API). We applied this process successfully to prepare more than 17 kg (3.0−3.6 kg per batch) of YLF466D to support its preclinical study.

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Advanced palladium free approach to the synthesis of substituted alkene oxindoles via aluminum-promoted Knoevenagel reaction

Abstract: A synthetic route for the synthesis of C24, as well as for the design of focused libraries of direct AMPK activators was developed based on a convergent strategy.

Cited by 14 publications

References 37 publications

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

Activating Effect of 3‐Benzylidene Oxindoles on AMPK: From Computer Simulation to High‐Content Screening

Treatment of chemoresistant cell lines with indolinone-based small molecules

Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator

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