Investigating C7 modified tetrandrine derivatives for synthesis anti-hepatocellular carcinoma activity and mechanistic insights

Hepatocellular carcinoma (HCC) remains a significant global health challenge, with drug therapy being a critical treatment approach. However, the development of drug resistance and the occurrence of adverse reactions to existing medications have made the creation of new HCC treatments urgent. Tetrandrine, a bisbenzylisoquinoline alkaloid from natural products, has shown great potential in this area. Yet, systematic comparative studies on different tetrandrine modification sites (such as C-7 and C-14) are lacking, which has hindered the simultaneous optimization of its antitumor activity and synthetic feasibility. In this study, we focused on a C-7 modification strategy and designed and synthesized 38 novel tetrandrine sulfonate derivatives (including 31 new compounds) through an efficient one-step reaction. The in vitro antiproliferative activities of these derivatives were evaluated against four HCC cell lines (HepG-2, SMMC-7721, SK-Hep-1, and QGY-7701), and a systematic comparison with previously reported C-14 sulfonate derivatives was conducted. The results showed that all the C-7 derivatives exhibited good antiproliferative activities against HCC. Notably, compound 15 demonstrated significant antiproliferative activity against all tested cell lines, with IC₅₀ values ranging from 3.28 to 6.16 µM, which is superior to the first-line clinical drug 5-fluorouracil. Mechanistic studies revealed that compound 15 exerts its antitumor effects by regulating the balance of Bcl-2 and Bax proteins, triggering the release of cytochrome C from mitochondria, and subsequently activating the caspase-3-dependent apoptosis pathway. The results of target prediction showed that PDGFRA, FLT1, PIK3CD and MET might be the main targets of compound 15 against hepatocellular carcinoma. Although C-14 sulfonate derivatives showed slightly higher in vitro activity, C-7 derivatives (particularly compound 15) exhibited significant advantages in synthetic efficiency (one-step reaction), ease of purification, environmental friendliness, and scalability for industrial production. In conclusion, this study has established C-7 sulfonation as an efficient strategy for developing tetrandrine-based anti-HCC agents. With its remarkable antitumor activity, excellent synthetic process characteristics, and clear apoptosis-inducing mechanism, compound 15 has emerged as a highly promising clinical candidate. This C-7 modification platform provides a viable path for transforming natural product derivatives into clinical therapies for HCC treatment.