63514-80-7

Upstream product

• 123-54-6 acetylacetone 
• 27171-88-6 ethyl 2-chloro-(4-tolylhydrazono)acetate 
• 132815-69-1 (Z)-ethyl-2-chloro-2-(2-(p-tolyl)-hydrazono)acetate 
• 16382-10-8 ethyl 2-[2-(4-methylphenyl)hydrazinylidene]propanoate 
• 106-49-0 p-toluidine 
• 609-15-4 ethyl 2-chloro-3-oxo-butyrate 
• 623-73-4 diazoacetic acid ethyl ester 
• 459-44-9 4-methylbenzenediazonium tetrafluoroborate 
• 58670-19-2 bromo-p-tolylhydrazono-acetic acid ethyl ester 

Relevant academic research and scientific papers

Discovery of Novel PDEδDegraders for the Treatment of KRAS Mutant Colorectal Cancer

KRAS-PDEδprotein-protein interaction represents an appealing target for cancer therapy. However, fast release of high-affinity inhibitors from PDEδhampered drug binding affinity and antiproliferative activity. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules targeting PDEδwere designed. By employment of PDEδinhibitor deltazinone (2) and cereblon ligand pomalidomide (6), a series of potent PROTAC PDEδdegraders were obtained. The most promising compound 17f efficiently induced PDEδdegradation and demonstrated significantly improved antiproliferative potency in KRAS mutant SW480 cells. Compound 17f also achieved significant tumor growth inhibition in the SW480 colorectal cancer xenograft model. This proof-of-concept study provided a new strategy to validate the druggability of KRAS-PDEδinteraction and offered an effective lead compound for the treatment of KRAS mutant cancer.

In Situ Generation of Nitrilimines from Aryldiazonium Salts and Diazo Esters: Synthesis of Fully Substituted Pyrazoles under Room Temperature

A novel one-pot synthesis for fully substituted pyrazoles has been well developed via the in situ generation of nitrilimines from aryldiazonium salts and diazo esters and a subsequent cycloaddition with 1,3-dicarbonyl compounds. High yields, mild conditio

Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site

The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras–PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity. We delineate the structure–property relationship and in vivo pharmacokinetic (PK) and toxicokinetic (Tox) studies for pyrazolopyridazinone-based K-Ras–PDEδ inhibitors. These findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic Ras.

Pyridazinones for the treatment of cancer

The present invention relates to novel substituted pyrrolo- and pyrazolopyridazinones, as well as pharmaceutical compositions containing at least one of these substituted pyrrolo- and pyrazolo- pyridazinones together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said novel substituted pyrrolo- and pyrazolo- pyridazinones are binding to the prenyl binding pocket of PDEδ and therefore, are useful for the prophylaxis and treatment of cancer by inhibition of the binding of PDEδ to K-Ras and of Ras signaling in cells.

1,3-Dipolar Cycloaddition of Four Hydrazonoyl Chlorides to β-Diketones and α,β-Unsaturated Ketones

The 1,3-dipolar cycloaddition of four hydrazonoyl chloride derivatives with the sodium salt of unsymmetrical β-diketones (benzoylacetone) offers a versatile method for the regioselective synthesis of 2H-pyrazoles in a similar fashion to the cycloaddition of the nitrilimides with α,β-unsaturated ketones and esters. The structures of the prepared isomeric pyrazole and pyrazoline derivatives were established by spectroscopic and chemical methods.

The Regioselectivity of the 1,3-Dipolar Cycloaddition of α-Carbonylformonitrile N-arylimides To Benzylideneacetone and β-Diketones

The cycloaddition of the ethoxycarbonylformonitrile N-arylimides 2 to benzylideneacetone afforded two regioisomers, 5-acetyl- and 4-acetyl-dihydropyrazole but the cycloaddition of 2 to benzoylacetone afforded two regioisomers, 4-acetyl- and 4-benzoylpyrazole.Also, some pyrazolopyridazin-7-one and pyrazolopyridazinderivatives were synthesized.

Studies on Nitrile Imines : Synthesis of Pyrazoles Using Active Methylene Compounds

A series of C-ethoxycarbonyl and C-acetyl derivatives of hydrazidoyl halides have been prepared and reacted with carbanions of active methylene compounds to afford substituted pyrazoles (II and III) in good yields.The formation of pyrazoles involves the alkylation of active methylene group by hydrazidoyl halides to give the acyclic hydrazones, which then undergo cyclization to give the corresponding pyrazoles.The structural assignments of the products are based on spectral and chemical evidences.