Design, synthesis, and biological evaluation of novel chrysin derivatives as poly(ADP-ribose) polymerase 1 (PARP1) inhibitors for the treatment of breast cancer
- Chin J Nat Med. 2024 May;22(5):455-465. doi: 10.1016/S1875-5364(24)60642-4.
- 1. Hengyang Medical School, University of South China, Hengyang 421200, China; Emergency Department, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China.
- 2. Emergency Department, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China.
- 3. Hemato-oncology Department, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China.
- 4. Department of Breast and Thyroid Surgery, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China.
- 5. Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China.
- 6. Hengyang Medical School, University of South China, Hengyang 421200, China; Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang 421200, China. Electronic address: [email protected].
In this study, we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly (ADP-ribose) polymerase 1 (PARP1). Among these derivatives, compound 5d emerged as the most effective chrysin-based inhibitor of PARP1, with an IC50 value of 108 nmol·L-1. This compound significantly inhibited the proliferation and migration of Breast Cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage. Furthermore, 5d induced Apoptosis and caused an extended G1/S-phase in these cell lines. Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1. In vivo, in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type Breast Cancer.