ml-233

novel APJ agonist

ML233 is a potent non-peptide apelin receptor agonist (EC50 = 3.7 μM) that exhibits more than 21-fold selectivity over the closely related angiotensin 1 receptor (AT1) (>79 μM) [1].

Sirtuins (SIRTs) represent a distinct class of trichostatin A-insensitive lysyl-deacetylases (class III HDACs). Human SIRT1 is the homolog of yeast silent information regulator 2 (Sir2) and has been shown to regulate the activity of the p53 tumor suppressor and inhibit apoptosis. Small molecule activators of SIRT1, such as resveratrol, extend lifespan in yeast and C. elegans in a manner that resembles caloric restriction. CAY10591 has been identified as an activator of the enzyme SIRT1. This compound increases fluorescence by 233% in a SIRT1 activity assay. [Activator activity was defined as the percentage of signal increase relative to signal window in the following formula: 100 x (Sample - Signallow)/(Signalhigh - Signallow)]. CAY10591 suppresses TNF-α in a dose-dependent manner. In THP-1 cells, TNF-α levels decreased from 325 pg/ml (control) to 104 and 53 pg/ml with 20 and 60 µM CAY10591, respectively. This activator also has a significant dose-dependent effect on fat mobilization in differentiated adipocytes, which would indicate the potential of SIRT1 activators for anti-obesity or anti-diabetic purposes.

Antibacterialagent 233(Compound 7c)在多方面展示了显著的抗菌和抗肿瘤特性.首先,该化合物对Helicobacter pylori有明显的抑制效果,其MIC值介于0.4-1.6 μg mL.此外,Antibacterialagent 233能有效抑制刀豆脲酶(jack bean urease),IC50值为0.27 μg mL,并能改变H. pylori的细胞膜通透性,导致细胞内容物的渗漏.在体外环境中,该化合物在全血和人工胃液中显示出良好的代谢稳定性.在生物医学研究中,Antibacterialagent 233还在小鼠体内展现对U2OS肿瘤细胞的抑制活性.