Discovery of novel xanthohumol C derivatives regulating XRCC2 transcription and expression for the treatment of colorectal cancer.

X-ray repair cross-complementing 2 (XRCC2), a critical protein in homologous recombination (HR), plays a significant role in the occurrence, progression, and drug resistance of colorectal cancer (CRC). In this study, a series of xanthohumol C derivatives were synthesized, and their anticancer activity was evaluated. The results revealed that A33 demonstrated the potent anticancer activity and effectively inhibited the proliferation of CRC cells in vitro. Mechanistic investigations revealed that A33 suppressed the transcription and expression of XRCC2, resulting in cell cycle delay and the accumulation of DNA damage, ultimately leading to cell proliferation inhibition. Furthermore, A33 displayed high safety, favorable bioavailability (F = 37.51 %), and potent tumor growth inhibition in vivo, which highlighting its potential as a candidate for the development of novel anti-CRC therapies.