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

Abstract 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.