New synthetic AICAR derivatives with enhanced AMPK and ACC activation

Abstract

5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5 0 -phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5 0 -AMP activated protein kinase a (AMPKa), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and downregulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24 h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1 mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases.

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

“…However, no studies have been published to date using AICAR in animal models of DOX cardiotoxicity in vivo. AICAR has a short half-life and has to be administered intravenously, which along with some side effects such as hypoglycaemia and bradycardia makes its clinical use challenging [145], though new synthetic AICAR derivatives with increased stability and AMPK activation potential are being synthesised [146]. Furthermore, AICAR has AMPK-independent effects, which means that off-target effects are likely, making specific AMPK activators potentially more attractive for clinical use [147].…”

5′-Chloro-5′-deoxy-2′,3′-O-isopropylidene-6-fluoro nebularine

“…The high-performance liquid chromatography (HPLC) was performed on a UP-2075 Plus pump equipped with a UV-2075 Plus UV detector (Jasco, Cremella, Italy) using a 5 µm, 250-10 Si column (Purosphere ® STAR, Merck, Darmstadt, Germany) eluted with n-hexane/AcOEt, 6:4 with a flow rate of 2.0 mL/min. 5 -Chloro-5 -deoxy-2 ,3 -O-isopropylidene-6-fluoro nebularine (8). To a stirred solution of 4 (0.28 g, 0.86 mmol) in dry THF (7.5 mL), TsF (0.30 g, 1.7 mmol) and TBAF (2.6 mL of a 1.0 M solution in dry THF, 2.6 mmol) were added and the mixture refluxed for 16 h (TLC monitoring: n-hexane/AcOEt; 1:1).…”

“…The nucleoside AICAR (1, Figure 1), besides being an intermediate involved in purine biosynthesis, is an activator of the enzyme adenosine monophosphate-activated protein kinase (AMPK) in the 5 -phosphorylated form [7,8]. This activation leads to a cascade of metabolic events, such as the inhibition of basal and insulin-stimulated glucose uptake, lipogenesis, and glucose oxidation [9].…”

“…For example, the replacement of OH groups of sugar moieties with the isosteric F atom has generated life-saving drugs for the treatment of infectious diseases, such as HIV [4], HBV [5], and HCV [6]. The nucleoside AICAR (1, Figure 1), besides being an intermediate involved in purine biosynthesis, is an activator of the enzyme adenosine monophosphate-activated protein kinase (AMPK) in the 5′-phosphorylated form [7,8]. This activation leads to a cascade of metabolic events, such as the inhibition of basal and insulin-stimulated glucose uptake, lipogenesis, and glucose…”

Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action

“…This enzyme is one of the targets of AMPK. The phosphorylation of this enzyme causes its inactivation, and this leads to an increase in the oxidation of free fatty acids [16]. The phosphorylation of ACC indicates that analogues induce the phosphorylation (activation) of AMPK, which leads to modification of the different metabolic pathways.…”