Design, synthesis and anti-tumor efficacy evaluation of novel 1,3-diaryl propane-based polyphenols obtained from Claisen rearrangement reaction

Optimized double Claisen rearrangement reaction facilitates quick access to new polyphenols 2–5. Among them, 2t and 3t show promising anti-tumor efficacy in COLO205 xenografted mice model at a dosage of 150 mg/kg or 75 mg/kg. The results warrant further investigation of this series of compounds for CRC treatment. [Display omitted] •Inspired by the broad biological activities of clinical stage polyphenols such as Nordihydroguaiaretic acid, a series of 1,3-diaryl propane-based polyphenols represented by 2 and 3 were designed and synthesized.•Double Claisen rearrangement conditions were developed as the key step to access the designed polyphenols.•Screening of 49 polyphenols revealed that they have broad spectrum anticancer activity.•Among them, compounds 2 t and 3 t exhibited promising antitumor efficacy in COLO205 xenografted mice model with TGI of 58% (2 t, 150 mg/kg), 54% (3 t, 150 mg/kg) and 38% (3 t, 75 mg/kg), respectively. Polyphenols such as resveratrol, honokiol and nordihydroguaiaretic acid are widely existing in nature products or synthetic compounds with interesting biological activities. Inspired by their structural feature, a total of 49 1,3-diaryl propane-based polyphenols were designed and synthesized through Claisen rearrangement reaction. New compounds were initially assessed for their anti-proliferative activities against various cancer cell lines (PC-3, U87MG, U251, HCT116) at a concentration of 50 μM, and the results guided the SAR of this series of compounds. Further screening of selected compounds against seven cancer cell lines (three additional colon cancer cell lines namely COLO205, HT29 and SW480 were chosen) led to the identification of two advanced leads 2t and 3t with IC50 values ranging from 8.2 ± 0.1 to 19.3 ± 1.9 μM. Both compounds also showed promising anti-proliferative activities against COLO205 in dose- and time-dependent manners. Furthermore, 2t and 3t exhibited good anti-tumor efficacy in COLO205 xenografted mice model with TGI values ranging from 38% to 58%. These results warrant the further investigation of this series of compounds.