Li, Zhanhui published the artcileDesign, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity, COA of Formula: C6H4N2, the main research area is pyrrolidine preparation antitumor metastatic activity lipophilicity antagonist; Antagonist; CXCL12; CXCR4; Chemokine; GPCR.
The design, synthesis and evaluation of novel CXCR4 antagonists were based on a pyrrolidine scaffold e.g., 3-(1,3-dioxolan-2-yl)-1-(3-methylpyridin-2-yl)propan-1one. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by (S)-2-methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine, which displayed potent binding affinity to CXCR4 receptor (IC50 = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC50 = 0.25 nM). Moreover, in a transwell invasion assay, (S)-2-methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine significantly mitigated CXCL12/CXCR4 mediated cell migration. The (S)-2-Methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine exhibited good physicochem. properties (MW 367, logD7.4 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC50 > 30μM and minimal CYP isoenzyme inhibition). Importantly, (S)-2-methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine displayed much improved metabolic stability in human and rat liver microsomes. Lastly, (S)-2-Methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine demonstrated marked efficacy in a cancer metastasis model in mice. These results strongly support (S)-2-methyl-4-(4-methylpiperazin-1-yl)-6-((2-(3methylpyridin-2-yl)pyrrolidin-1-yl)methyl)pyrimidine as a prototypical lead for the development of promising CXCR4 antagonists as clin. candidates.
European Journal of Medicinal Chemistry published new progress about Antitumor agents. 100-70-9 belongs to class nitriles-buliding-blocks, name is Picolinonitrile, and the molecular formula is C6H4N2, COA of Formula: C6H4N2.
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts