Diversity-enhancing synthesis of novel arylnaphthalene lignan and hexahydrobenzo[k]phenanthridine analogues and identification of a potent antitumor lead.

A diversity-enhancing strategy was developed to construct 25 novel arylnaphthalene lignan and 5,6,7,7a,8,13b-hexahydrobenzo[k]phenanthridine analogues derived from sesamin. Notably, the 5,6,7,7a,8,13b-hexahydrobenzo[k]phenanthridine scaffold is reported here for the first time. The mechanism of the key diversity-enhancing reaction (DER) was systematically elucidated, and the absolute configuration of compound 13a was unambiguously assigned as 6aS,7aR,8S,13bR by single-crystal X-ray diffraction using Cu Kα radiation combined with specific rotation data and comparison with the known configuration of compound 7. Biological screening in human hepatocellular carcinoma (HCC) Huh7 cells revealed that several derivatives (compounds 8, 12b, 12c, and 15a-15f) exhibited promising antiproliferative activity. Compound 8 displayed the most potent activity with an IC50 value of 8.23 μM, superior to sorafenib and cisplatin. Further mechanistic studies demonstrated that compound 8 induced dose- and time-dependent growth inhibition and G2/M-phase cell cycle arrest in HCC cells. In a Huh7 xenograft mouse model, compound 8 significantly suppressed tumor growth without obvious body weight loss, showing favorable in vivo efficacy and safety. This work not only enriches the structural diversity of lignan-based small molecules but also identifies compound 8 as a promising antitumor lead worthy of further development. The diversity-enhancing approach proved effective for the discovery of structurally novel and biologically active natural product derivatives.