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.

中文翻译：

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具有高效心脏保护作用的新型 SIRT3 激活剂异甜菊醇衍生物的设计、合成和体内评价

心血管疾病（CVD）仍然是导致死亡的主要原因，这促使人们探索创新药物。线粒体功能障碍是心血管疾病发展的关键因素。 Sirtuin 3 (SIRT3) 是一种重要的线粒体脱乙酰酶，以其在保护线粒体免受损伤和功能障碍方面的关键作用而闻名，已成为 CVD 治疗的一个有前途的治疗靶点。利用异甜菊醇（一种天然对映贝叶烯二萜类化合物）合成了 24 种衍生物，并使用斑马鱼模型进行了体内评估，建立了推论的结构-活性关系。其中，衍生物5v在斑马鱼和小鼠模型中对阿霉素诱导的心肌病表现出显着疗效。随后的研究表明，5v选择性升高SIRT3表达，导致SOD2和OPA1表达上调，有效预防线粒体功能障碍，减轻氧化应激，保持心肌细胞活力。作为一种新型结构的 SIRT3 激活剂，具有强大的治疗效果，5v成为进一步药物开发的有希望的候选者。