131364-74-4Relevant academic research and scientific papers
Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition
Sahin, Zafer,Biltekin, Sevde Nur,Yurttas, Leyla,Berk, Barkin,?zhan, Ya?mur,Sipahi, Hande,Gao, Zhan-Guo,Jacobson, Kenneth A.,Demirayak, ?eref
, (2021/01/12)
Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 μM, which is slightly higher activity than cisplatin (1.67 μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 μM; 5f: 0.97 μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.
Potent 5-Cyano-6-phenyl-pyrimidin-Based Derivatives Targeting DCN1-UBE2M Interaction
Zhou, Wenjuan,Ma, Liying,Ding, Lina,Guo, Qian,He, Zhangxu,Yang, Jing,Qiao, Hui,Li, Lingyu,Yang, Jie,Yu, Shimin,Zhao, Lili,Wang, Shaomeng,Liu, Hong-Min,Suo, Zhenhe,Zhao, Wen
, p. 5382 - 5403 (2019/06/17)
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.
Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase
Dragovich, Peter S.,Fauber, Benjamin P.,Corson, Laura B.,Ding, Charles Z.,Eigenbrot, Charles,Ge, Hongxiu,Giannetti, Anthony M.,Hunsaker, Thomas,Labadie, Sharada,Liu, Yichin,Malek, Shiva,Pan, Borlan,Peterson, David,Pitts, Keith,Purkey, Hans E.,Sideris, Steve,Ultsch, Mark,Vanderporten, Erica,Wei, Binqing,Xu, Qing,Yen, Ivana,Yue, Qin,Zhang, Huihui,Zhang, Xuying
, p. 3186 - 3194 (2013/06/27)
A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC 50 = 8.1 μM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.48 μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.
Chemotherapeutic agents, XVIII: Synthesis of pi-deficient pyrimidines and fused pyrimidines as leishmanicidal agents.
Ram
, p. 895 - 899 (2007/10/02)
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.
