19171-18-7

Usage

Uses

Used in Pharmaceutical Industry:
2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione is used as an intermediate compound in the synthesis of various pharmaceuticals. Its unique structure allows it to be a key component in the development of new drugs with specific therapeutic properties.
Used in the Preparation of Pomalidomide:
Specifically, 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione is involved in the preparation of Pomalidomide (P688200), a thalidomide derivative. Pomalidomide is a potent inhibitor of TNF-α production, which makes it a valuable compound in the treatment of various inflammatory and autoimmune diseases.

InChI:InChI=1/C13H9N3O6/c17-9-5-4-8(11(18)14-9)15-12(19)6-2-1-3-7(16(21)22)10(6)13(15)20/h1-3,8H,4-5H2,(H,14,17,18)

Upstream product

• 85535-45-1 5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid 
• 31140-42-8 (RS)-(2,6-dioxopiperidin-3-yl)carbamic acid tert-butyl ester 
• 56-85-9 L-glutamine 
• 641-70-3 3-nitrophthalic acid anhydride 
• 151367-92-9 L-tert-butyl N-[2,6-dioxohexahydro-3-pyridinyl] Carbamate 
• 13726-85-7 Boc-Gln-OH 
• 603-62-3 4-nitro-1H-isoindole-1,3(2H)-dione 
• 590365-46-1 aminoglutarimide trifluoroacetate 
• 496-12-8 isoindoline 
• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 6383-80-8 2-(3'-Nitro-phthalimido)-glutarsaeureanhydrid 
• 18636-08-3 1-(4-nitro-1,3-dioxoisoindolin-2-yl)propane-1,3-dicarboxylic acid 
• 617-65-2 Glutamic acid 
• 118061-00-0 (3S)-3-aminopiperidine-2,6-dione hydrobromide 

Downstream Products

• 19171-19-8 pomalidomide 
• 444287-84-7 2‐chloro‐N‐(2‐(2,6‐dioxopiperidin‐3‐yl)‐1,3‐dioxoisoindolin‐4‐yl)acetamide 
• 847871-99-2 3-(4-amino-1-oxo-1,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione hemihydrate 
• 202271-89-4 (R)-(+)-4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3-dione 
• 202271-89-4 (S)-(-)-4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3-dione 
• 879126-98-4 Lenalidomide 

Relevant academic research and scientific papers

Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway

As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via “click reaction” to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments.

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.

New synthesis route for the preparation of pomalidomide

A new route for the preparation of pomalidomide is described in the study. The synthetic procedure starts from 4-nitroisobenzofuran-1,3-dione and 3-aminopiperidine-2,6-dione hydrochloride via a three-step reaction resulting in a total yield of 65% with a high-performance liquid chromatographic (HPLC) purity of 99.56% and a low palladium residue level of 2?ppm. This method can be deemed as an efficient, practical, and environmentally friendly synthetic route for the preparation of pomalidomide.

Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application

The present work deals with the synthesis of a new series of thalidomide derivatives for therapeutic applications. These compounds were evaluated in vitro on a human endothelial cell line EA.hy926 for their antiproliferative potential and in vivo on an experimental animal multiple sclerosis model called EAE as angiogenesis inhibitors. The preliminary results obtained on EAE assays seem to validate that anti-angiogenesis compounds could be promising tools for the treatment of MS.

Rational Design and Synthesis of HSF1-PROTACs for Anticancer Drug Development

PROTACs employ the proteosome-mediated proteolysis via E3 ligase and recruit the natural protein degradation machinery to selectively degrade the cancerous proteins. Herein, we have designed and synthesized heterobifunctional small molecules that consist of different linkers tethering KRIBB11, a HSF1 inhibitor, with pomalidomide, a commonly used E3 ligase ligand for anticancer drug development.

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.

Synthesis process for continuously preparing pomalidomide by using microchannel reactors

The invention discloses a synthesis process for continuously preparing pomalidomide by using microchannel reactors. The synthesis process comprises the following steps tha (1) 3-nitrophthalic acid isdissolved in acetic anhydride, and a reaction is performed to obtain 3-nitrophthalic anhydride; (2) 3-nitrophthalic anhydride is dissolved in formic acid to prepare a homogeneous solution A; (3) 3-aminopiperidine-2,6-dione is dissolved in ammonium formate and formic acid to prepare a homogeneous solution B; (4) palladium on carbon and methanol are prepared into suspension C; (5) the homogeneous solution A and the homogeneous solution B are simultaneously pumped into a microstructured mixer I in a microchannel reaction device separately, and after mixing, the mixture is introduced into a microstructured reactor I; (6) the suspension C and an effluent from the microstructured reactor I are simultaneously pumped into a microstructured mixer II in the microchannel reaction device separately while the step (5) is carried out, and after mixing, the mixture is introduced into a microstructured reactor II; and (7) an effluent from the microstructured reactor II is collected to obtain pomalidomide.

DIMERIC IMMUNO-MODULATORY COMPOUNDS AGAINST CEREBLON-BASED MECHANISMS

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

De-novo design of cereblon (CRBN) effectors guided by natural hydrolysis products of thalidomide derivatives

Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.