Structure–activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53–hDM2 inhibitors

The cyclization of amides derived from ethenetricarboxylic acid bearing tert‐amino groups has been examined. The amides were efficiently converted to piperidine derivatives (2‐piperidones) upon heating in a polar solvent (e. g., DMSO or DMF) via intramolecular hydride transfer and subsequent ring closure. The reaction was less efficient in the presence of a Lewis acid. The reactivity varies depending on the alkyl substituents of tert‐amino groups, probably due to steric effects. The hydride transfer/cyclization mechanism was investigated by DFT calculations. The reaction of the carboxylic acid and relatively bulky diamines such as diisopropyl‐substituted diamine in the presence of amide condensation reagents at 60 °C gave the piperidine derivatives in a one‐pot reaction. The reaction of the diisopropylamine substituted piperidine product with primary amines gave secondary amine‐substituted piperidines.

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Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp³ Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Yamazaki

Naito

Tatsumi

et al. 2018

ChemistrySelect

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Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability

Tian

Lahue

et al. 2022

Bioorganic & Medicinal Chemistry Letters

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p53: An Attractive Therapeutic Target for Cancer

Patel

2020

CMC

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Cancer is a leading cause of death worldwide. It initiates when cell cycle regulatory genes lose their function either by environmental and/or by internal factors. Tumor suppressor protein p53, known as “Guardian of genome”, plays a central role in maintaining genomic stability of the cell. Mutation of TP53 is documented in more than 50% of human cancers, usually by overexpression of negative regulator protein MDM2. Hence, reactivation of p53 by blocking the protein-protein interaction between the murine double minute 2 (MDM2) and the tumor suppressor protein p53 has become the most promising therapeutic strategy in oncology. Several classes of small molecules have been identified as potent, selective and efficient p53-MDM2 inhibitors. Herein, we review the druggability of p53-MDM2 inhibitors and their optimization approaches as well as clinical candidates categorized by scaffold type.

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Structure–activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53–hDM2 inhibitors

Cited by 3 publications

References 22 publications

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp³ Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp³ Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability

p53: An Attractive Therapeutic Target for Cancer

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Structure–activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53–hDM2 inhibitors

Cited by 3 publications

References 22 publications

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp3 Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp3 Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability

p53: An Attractive Therapeutic Target for Cancer

Contact Info

Product

Resources

About

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp³ Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp³ Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization