A natural product-hybridization approach toward anticancer drug discovery: synthesis and antitumor evaluation of CTBC6, designed from sulforaphane and magnolol.

Natural products, with their promising drug-like profiles, inherent pharmacological potential, and a vast reservoir of privileged structures, have long been recognized as a rich source of hit compounds in anticancer drug discovery. Building upon our group's prior work, this study delves into the medicinal chemistry of sulforaphane (SFN)-a star molecule in anticancer research, leading to the discovery of CTBC6 as a novel small molecule anticancer compound. We demonstrated that CTBC6 exhibited potent anti-breast cancer effects both in vitro and in vivo with no significant organ toxicity. We investigated the anti-breast cancer function of the hit hybrid compound CTBC6, and found that CTBC6 induced apoptosis and caused cell cycle arrest at the G2/M phase, while also effectively suppressing cell migration. Moreover, transcriptome analysis and the mechanistic studies revealed that CTBC6 may impede breast cancer progression by inhibiting MEK/ERK signaling pathway. Importantly, the functional targets of CTBC6 in breast cancer was assessed. Through chemical proteomics, we identified CNOT10 and STAT5A as potential direct targets through which CTBC6 exerts its anti-breast cancer activity. Our study lays a good foundation for further medical research of sulforaphane and its derivatives, and also presents a new strategic paradigm for natural product-driven anticancer drug discovery.