A Nucleoside Analogue Bearing a C2′-Stereogenic All-Carbon Quaternary Center for the Treatment of Heart Failure

Heart failure (HF) is a significant global health burden with a high mortality rate and no curative or preventative treatment. Many factors can contribute to HF development, including hemodynamic factors and chemotherapy-induced cardiotoxicity. Loss of cardiomyocytes triggers cardiac remodeling and HF, suggesting that strategies aimed at preserving cardiomyocyte survival could provide therapeutic benefits. Here, we describe the biological activity of an adenosine-like nucleoside analogue bearing an all-carbon stereogenic quaternary center that induces a conformational bias to enhance both activity and selectivity. The lead compound, LCB-2122, prevents cardiomyocyte death both <i>in vitro</i> and <i>in vivo</i> in an animal model of acute chemotherapy-induced HF. This protective effect against chemotherapy-induced cardiomyocyte loss is linked to AMPK activation and is abrogated by siRNA-mediated reduction of AMPK expression. The results suggest that targeting cardiomyocyte survival with conformationally biased nucleoside analogues may offer a promising avenue for preventing cardiac dysfunction and the progression of HF.