Cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018, and this burden continues to increase. Therefore, there is a clear and urgent need for novel drugs with increased efficacy for the treatment of different cancers. Previous research has demonstrated that brevilin A (BA) exerts anticancer activity in various cancers, including human multiple myeloma, breast cancer, lung cancer, and colon carcinoma, suggesting the anticancer potential present in the chemical scaffold of BA. Here, we designed and synthesized a small library of 12 novel BA derivatives and evaluated the biological anticancer effects of the compounds in various cancer cell lines. The results of this structure–activity relationship study demonstrated that BA derivatives BA-9 and BA-10 possessed significantly improved anticancer activity toward lung, colon, and breast cancer cell lines. BA-9 and BA-10 could more effectively reduce cancer cell viability and induce DNA damage, cell-cycle arrest, and apoptosis when compared with BA. Our findings represent a significant step forward in the development of novel anticancer entities.

Selectively activating the distal inactive C-H bond for functionalization is one of the on-going challenge in organic synthetic chemistry. In recent years, benefiting from the development of selective synthesis methods, novel methodologies not only make it possible to break non-traditional chemical bonds and attain more diversity in inactive sites, but also provide more possibilities for the diversification of complex natural products. Direct C-H bond functionalization approaches make it feasible to explore structure-activity relationship (SAR), generate metabolites and derivatives, and prepare biological probes. Among them, direct oxidation of inert C-H bonds is one of the most common methods for natural product diversification. In this review, we focus on the application of remote functionalization of inert C-H bonds for natural products derivatization, including the establishment of oxidation methods, the regulation of reaction sites, and the biological activities of derivatives. We highlight the challenges and opportunities of remote functionalization of inert C-H bonds for natural product diversification through selected and representative examples. We try to show that inert C-H bond oxidation, properly regulated and optimized, can be a powerful and efficient strategy in both synthetic and medicinal chemistry.