131364-40-4

Upstream product

• 131364-74-4 5-Cyano-6-(3,4-dichlorophenyl)-2-thiouracil 
• 131364-74-4 C₁₁H₅Cl₂N₃OS 
• 106-96-7 propargyl bromide 
• 6287-38-3 3,4-dichlorobenzaldehyde 

Relevant academic research and scientific papers

Potent 5-Cyano-6-phenyl-pyrimidin-Based Derivatives Targeting DCN1-UBE2M Interaction

Neddylation of the Cullin-RING E3 ligases (CRLs) regulates the homeostasis of approximately 20% of cellular proteins. Defective in cullin neddylation 1 (DCN1), as a co-E3 ligase, interacts with UBE2M to enhance the activation of CRLs, and this interaction is emerging as a therapeutic target for human diseases. Here, we present a series of pyrimidin-based small molecular inhibitors targeting DCN1-UBE2M interaction. After finding a novel inhibitor DC-1 with IC50 = 1.2 μM, we performed a series of chemical optimizations, which finally led to the discovery of a potent thiazole containing 5-cyano-6-phenylpyrimidin-based inhibitor DC-2 (IC50 = 15 nM). Next, using protein and cellular thermal shift assays, coimmunoprecipitation, molecular docking, and site-specific mutation experiments, we further proved that DC-2 specifically inhibited the interaction of UBE2M and DCN1 at molecule and cellular levels, resulting in the decrease of cullin3 neddylation and accumulation of its substrate, NRF2. Our findings indicate that DC-2 may serve as a novel lead compound for specific derivatives targeting DCN1-UBE2M interaction.

Chemotherapeutic agents, XVIII: Synthesis of pi-deficient pyrimidines and fused pyrimidines as leishmanicidal agents.

Synthesis of 6-aryl-5-cyano-2-thiouracils 1a-d from the condensation-cyclization of an aromatic aldehyde, thiourea and ethyl cyanoacetate has been described. Alkylation of 1a-d under different reaction conditions with mono- and dihalo-alkanes yielded 2, 3, and 6. Interaction of 1 with POCl3 provided halopyrimidines 8a,b. Nucleophilic substitution on 8 and 3 with aromatic amines gave 9a-d and 7a-d respectively. 6-Chloro-5-nitro-3-methyluracil (11) obtained by nitration of 10 underwent nucleophilic substitution with amines providing 12. Some of the compounds screened as leishmanicides did not exhibit any significant activity.