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

Authors

Abir Almazloum, Wael Maharsy, Starr Dostie, Fabiola Becerril-Jiménez, Carla Eymard, Hiba Komati, Louis Leblanc, Amarender Manchoju, Philippe Mochirian, Renaud Zelli, Michel Prevost, Mona Nemer, Yvan Guindon

Published in

Journal of medicinal chemistry. Dec 09, 2025. Epub Dec 09, 2025.

Abstract

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 in vitro and in vivo 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.

PMID:
41364793
Bibliographic data and abstract were imported from PubMed on 10 Dec 2025.

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