Efficient synthesis of neocryptotanshinone: Evaluation of acute toxicity and therapeutic efficacy against doxorubicin-induced cardiotoxicity.

OBJECTIVE: To develop an efficient one-pot synthesis of high-purity neocryptotanshinone (NCTS), assess its acute oral toxicity, and evaluate its protective effects against doxorubicin-induced cardiotoxicity. METHODS: NCTS was synthesized from cryptotanshinone by a one-pot reaction followed by silica gel purification and characterized using NMR, HRMS, and HPLC. Acute oral toxicity was assessed according to OECD 420/423 guidelines. Cytotoxicity and cardioprotective effects of synthetic NCTS and a commercial reference standard were compared in vitro. Cardioprotection was further evaluated via an in vivo mouse model of doxorubicin-induced cardiotoxicity. RESULTS: NCTS was obtained at over 80% yield and over 99.0% purity. Its estimated LD₅₀ was 1000-1500 mg/kg. Toxic signs in surviving mice resolved within 48 h. No significant organ toxicity was detected at 1000 mg/kg, whereas hippocampal neuronal atrophy occurred only in male mice at doses above 1500 mg/kg. In vitro, NCTS showed cardioprotective activity comparable to the reference standard, while significant cytotoxicity appeared only at a higher concentration under the tested conditions. In vivo experiments confirmed that the NCTS could improve the cardiac function of mice with doxorubicin-induced cardiotoxicity, alleviate myocardial pathological damage, reduce reactive oxygen levels, and inhibit cell apoptosis. CONCLUSION: This study established an efficient one-pot synthesis of high-purity NCTS and provided preliminary evidence of its acute safety and cardioprotective activity, supporting further preclinical investigation.