Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects

Cardiovascular diseases (CVDs) persist
as the predominant
cause
of mortality, urging the exploration of innovative pharmaceuticals.
Mitochondrial dysfunction stands as a pivotal contributor to CVDs
development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase
known for its crucial role in protecting mitochondria against damage
and dysfunction, has emerged as a promising therapeutic target for
CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated
in vivo using a zebrafish model, establishing a deduced structure–activity
relationship. Among these, derivative 5v exhibited significant
efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine
models. Subsequent investigations revealed that 5v selectively
elevated SIRT3 expression, leading to the upregulation of SOD2 and
OPA1 expression, effectively preventing mitochondrial dysfunction,
mitigating oxidative stress, and preserving cardiomyocyte viability.
As a novel structural class of SIRT3 activators with robust therapeutic
effects, 5v emerges as a promising candidate for further
drug development.