42472-93-5

Usage

Molecular structure

A complex structure consisting of a piperidinedione ring with a methyl group and a 1,3-dioxoisoindolin-2-yl group attached.

Natural occurrence

Not naturally occurring.

Synthesis

Typically synthesized in a laboratory setting.

Potential applications

May have applications in pharmaceutical research and organic synthesis.

Research status

Further research is needed to fully understand its properties and potential uses.

InChI:InChI=1/C14H12N2O4/c1-15-11(17)7-6-10(14(15)20)16-12(18)8-4-2-3-5-9(8)13(16)19/h2-5,10H,6-7H2,1H3

Upstream product

• 74-89-5 methylamine 
• 3343-28-0 N-phthaloylglutamic acid anhydride 
• 31140-42-8 (RS)-(2,6-dioxopiperidin-3-yl)carbamic acid tert-butyl ester 
• 85-44-9 phthalic anhydride 
• 50-35-1 thalidomide 
• 74-88-4 methyl iodide 
• 67-56-1 methanol 
• 373-68-2 tetramethylammonium fluoride 

Relevant academic research and scientific papers

Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs

Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition cohigh efficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion. Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100°C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.

Chemical stabilities and biological activities of thalidomide and its N-aikyl analogs

Purpose. To determine whether the N-alkyl analogs of the thalidomide are active and stable, their stabilities in buffer and their abilities to inhibit tumor necrosis factor alpha (TNF-α) in vitro in human peripheral blood mononuclear cell cultures were investigated. Methods. TNF-α concentrations were determined with the aid of ELISA kits. Chemical stabilities of the compounds were determined in three phosphate buffer solutions (pH 6, 6.4, and 7.4) at 25 and 32°C by high-pressure liquid chromatography, and half-lives were calculated. Results. The addition of N-alkyl groups to the glutarimide ring of the thalidomide molecule had little effect on the ability such compounds have to inhibit TNF-α production. There was no statistical difference between the activity of thalidomide and its N-alkyl analogs at a 95% confidence level. Like thalidomide, the N-alkyl analogs in this series inhibit an average of 60% of the TNF-α synthesis in lipopolysaccharide-stimulated peripheral blood mononuclear cell cultures. Thalidomide and its N-alkyl analogs are hydrolyzed at very similar rates, with half-lives ranging from 25 to 35 h at 32°C at pH 6.4 and an average rate constant of 2.35 × 10-2/h. Conclusions. Alkylating thalidomide had little effect on its ability to inhibit the production of TNF-α in these cell cultures. All of the compounds tested seem to have some, perhaps comparable, therapeutic potential.

Selective Methylation of Amides, N-Heterocycles, Thiols, and Alcohols with Tetramethylammonium Fluoride

We herein disclose the use of tetramethylammonium fluoride (TMAF) as a direct and selective methylating agent of a variety of amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification. Our computational studies suggest a concerted methylation-deprotonation as the preferred reaction pathway.

Homo-PROTACs for the Chemical Knockdown of Cereblon

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation. The homodimerized compound 15a was characterized as a highly potent and efficient CRBN degrader with only minimal effects on IKZF1 and IKZF3. The cellular selectivity of 15a for CRBN degradation was confirmed at the proteome level by quantitative mass spectrometry. Inactivation by compound 15a did not affect proliferation of different cell lines, prevented pomalidomide-induced degradation of IKZF1 and IKZF3, and antagonized the effects of pomalidomide on multiple myeloma cells. Homobifunctional CRBN degraders will be useful tools for future biomedical investigations of CRBN-related signaling and may help to further elucidate the molecular mechanism of thalidomide analogues.

AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION

This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

SMALL MOLECULES AGAINST CEREBLON TO ENHANCE EFFECTOR T CELL FUNCTION

Disclosed are small molecules against cereblon to enhance effector T cell function. Methodos of making thes molecules and methods of using them to treat various disease states are also disclosed.