Design, Synthesis, and Evaluation of Novel Cryptotanshinone Derivatives for Activity against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) can be difficult to treat because of resistance to existing therapeutic agents. Our prior studies revealed the inhibitory effect of the natural product cryptotanshinone (CTS) on the proliferation of TNBC cells; however, its clinical application was prevented due to its low water solubility and activity. This study aimed to synthesize derivatives of CTS with enhanced potency and water solubility. The structure of CTS was modified by adding amino acid side chains, which were derived into phosphonium salts. The derivatives were immersed in phosphate-buffered saline (PBS) to assess their water solubility. The antitumor effects of the derivatives against MDA-MB-231 breast cancer cells were assessed by evaluating their roles in regulating cell proliferation, cell apoptosis, and cell-cycle arrest using cell counting kit-8 (CCK-8), flow cytometry, and calcein-AM/propidium iodide assay, respectively. In this work, a total of 29 derivatives of CTS were synthesized, of which the tricyclohexylphosphine derivatives C4-2 and C5-2 were highly soluble in PBS, with 790- and 450-fold higher than that of CTS, respectively, and at the same time, the antitumor activities of C4-2 and C5-2 were also enhanced, with two- and fourfold higher than that of CTS, respectively. Further studies revealed that the compounds may inhibit the proliferation of MDA-MB-231 by inducing cellular arrest in the G2/M phase. These findings provided preliminary data for the mechanisms of CTS and its derivatives in blocking TNBC and suggested C4-2 and C5-2 as potential agents for the treatment of the disease in the future.