Breast cancer (BC) stands as the most prevalent malignancy among women worldwide, and approximately 15%–20% of breast cancer patients exhibit defects in the DNA repair pathway [1]. Poly (ADP-ribose) polymerase 1 (PARP1) serves as a core regulator of DNA damage repair, and its dysfunction is closely associated with breast cancer initiation, metastasis, and treatment resistance [2]. Concurrently, as a key enzyme in DNA double-strand break (DSB) repair, PARP1 maintains genomic stability through base excision repair (BER), rendering it a highly promising therapeutic target for cancer treatment [3]. Extensive research has also demonstrated that PARP1 inhibitors exhibit significant therapeutic efficacy against these DNA repair-deficient cancers [4]. Currently, PARP1 has attracted considerable attention as an anti-cancer therapeutic target in preclinical research and clinical trials [5], [6]. A number of PARP1 inhibitors have been approved to treat human malignancies, and numerous additional candidates are in clinical studies. For instance, drugs such as Olaparib (AZD2281), Veliparib (ABT-888), and Rucaparib (AG-014699) are primarily used to treat breast cancer, ovarian cancer, and solid tumors [7], [8].

Currently, research on natural small-molecule compounds and their applications in cancer therapeutics is progressively emerging as a focal point of intense scientific attention within pharmaceutical science [9], [10]. As a natural product, the distinct chemical properties of isoalantolactone—including alkylating reactivity (α-methylene-γ-lactone structure), lipophilicity, and unique molecular geometry with electronic features—collectively confer high bioactivity and pharmacological efficacy within biological systems [11]. This compound consistently exhibits inhibitory effects against multiple cancer cell types, including breast, gastric, and colon cancers [12]. However, the extremely low water solubility of isoalantolactone results in low bioavailability in vivo and severely restricts clinical therapeutic applications [13]. Thus, structural modifications of isoalantolactone and the establishment of meaningful structure-activity relationships are imperative.

In recent years, structural modification of sesquiterpene lactones featuring α-methylene-γ-lactone motifs via aza-Michael addition reactions has emerged as a popular area of investigation in medicinal chemistry [14]. Extensive studies demonstrate that amino derivatives of sesquiterpene lactones—featuring amino or heterocyclic amine groups within the α-methylene-γ-lactone scaffold—significantly enhance drug solubility while potentially preserving or augmenting the bioactivity of the parent molecule and reducing its cytotoxicity [15], [16], [17]. Patrushev et al. found that a derivative of isoalantolactone, 13E-(4-fluorophenyl)isoalantolactone, induces ROS-dependent death in MCF-7 cancer cells via mitochondrial apoptosis pathway [15]. Based on the aforementioned research background, this study intends to first investigate the binding mechanism of isoalantolactone to the PARP1 kinase structure using molecular docking technology. Then, based on this mechanism, it aims to predict potential structural modification sites within the isoalantolactone molecule, followed by the chemical synthesis of isoalantolactone derivatives using methods such as the Michael addition reaction. These derivatives will subsequently undergo in vitro activity and preliminary mechanism studies.