5466-00-2Relevant articles and documents
Formation of 5,6-cyclopentano-uracil by cyclization of the bisamide of adipic acid induced by oxalyl chloride
Bergman, Jan,Svensson, Per H.
, p. 4601 - 4603 (2010)
Cyclization of the bisamide of adipic acid induced by oxalyl chloride will eventually yield a product of the composition C9H8N2O5, which upon hydrolysis gave 5,6-cyclo-pentanouracil. The structures of both compounds were established by X-ray crystallography.
Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability
Knapinska, Anna M.,Singh, Chandani,Drotleff, Gary,Blanco, Daniela,Chai, Cedric,Schwab, Jason,Herd, Anu,Fields, Gregg B.
supporting information, p. 1133 - 1142 (2021/01/29)
Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.
Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors
Zhang, Yonglei,Xie, Xiaomin,Wang, Xueyuan,Wen, Tiantian,Zhao, Chi,Liu, Hailong,Zhao, Bo,Zhu, Yongqiang
, (2021/04/12)
Valine-containing protein (VCP) is a member of the adenosine triphosphate family involved in a variety of cellular activities. VCP/p97 is capable of maintaining protein homeostasis and mediating the degradation of misfolded polypeptides by the ubiquitin–proteasome system (UPS). In this manuscript, a series of novel p97 inhibitors with pyrimidine as core structure were designed, synthesized and biologically evaluated. Based on the enzymatic results, a detailed structure–activity relationship discussion of the synthesized compounds was carried out. Furthermore, cellular activities of the compounds with enzymatic potency of less than 200 nM were investigated by using A549 and RPMI8226 cell lines. Among the screened inhibitors, compound 17 (IC50, 54.7 nM) showed good enzymatic activity. Investigation of cellular activities with non-small cell lung cancer A549 and multiple myeloma (MM) RPMI8226 further confirmed the potency of 17 with the IC50 values of 2.80 μM and 0.86 μM, respectively. Compound 17 is now being developed as a candidate. Finally, docking studies were carried out to explore the possible binding mode between the active inhibitor 17 and p97.
Synthesis and evaluation of novel fused pyrimidine derivatives as GPR119 agonists
Fang, Yuanying,Xiong, Lijuan,Hu, Jianguo,Zhang, Shaokun,Xie, Saisai,Tu, Liangxing,Wan, Yang,Jin, Yi,Li, Xiang,Hu, Shaojie,Yang, Zunhua
, p. 103 - 111 (2019/01/28)
A novel series of fused pyrimidine derivatives were designed, synthesized and evaluated as GPR119 agonists. Among them, cyclohexene fused compounds (tetrahydroquinazolines) showed greater GPR119 agonistic activities than did dihydrocyclopentapyrimidine and tetrahydropyridopyrimidine scaffolds. Analogues (16, 19, 26, 28, 42) bearing endo-N-Boc-nortropane amine and fluoro-substituted aniline exhibited better EC50 values (0.27–1.2 μM) though they appeared to be partial agonists.
