Sana, Sravani published the artcileExploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect, Synthetic Route of 56-05-3, the publication is European Journal of Medicinal Chemistry (2020), 112457, database is CAplus and MEDLINE.
Here combined the two pharmacophoric units (pyrimidine and thioindole) combined in a single entity via mol. hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates I [R1 = morpholino, piperidin-1-yl, phenylamino, etc.; R2 = Ph, 4-methoxyphenyl, 4-chlorophenyl, etc.] compound I [R1 = pyrrolidin-1-yl; R2 = 4-chlorophenyl] was found to exhibited significant IC50 =5.85, 7.87, 6.41 and 10.43μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, resp. All these compounds I were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, I [R1 = morpholino, R2 = 2-methyl-4-chlorophenyl; R1 = piperidin-1-yl, R2 = 2,5-dimethylphenyl; R1 = pyrrolidin-1-yl, R2 = 4-chlorophenyl; R1 = pyrrolidin-1-yl, R2 = 2-methyl-4-chlorophenyl, R1 = 4-(pyridin-2-yl)piperazin-1-yl, R2 = 2-methyl-4-chlorophenyl; R1 = 4-benzylpiperazin-1-yl, R2 = Ph, 4-methoxyphenyl; R1 = cyclopropylamino, R2 = 2-methyl-4-chlorophenyl] prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the pos. control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarization of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by I [R1 = pyrrolidin-1-yl; R2 = 4-chlorophenyl] in a dose-dependent manner. Mol. docking studies also shown that compound I [R1 = pyrrolidin-1-yl; R2 = 4-chlorophenyl] capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
European Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C4H3Cl2N3, Synthetic Route of 56-05-3.
Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia