Evaluating Bis‐Phenacyl Bromide‐Based Bis‐Heterocyclic Templates as Anticancer Prototypes and Potential PARP1 Inhibitors
Year: 2025
Type: article
Abstract: Poly(ADP‐ribose) polymerase 1 (PARP1) plays a pivotal role in DNA damage repair and represents a promising antineoplastic target. Novel bis‐heterocyclic derivatives based on a bis‐phenacyl bromide scaffold were synthesized and assessed for their antineoplastic potential against eight malignant cell lines, and PARP1 inhibitory activity. These derivatives exhibited selective cytotoxicity toward MCF7 and PC‐3 cancer cell lines, while showing limited or no toxicity to other malignant cell lines. Derivatives 5a–e, 13, 18, 34, 35, and 36 (IC50 < 10 μM) were most effective against PC‐3 cells. Derivatives 5a, 5d, 5e, 12, 25, 28a and 34 demonstrated remarkable potency against MCF7 cells (IC50 = 0.006–0.417 μM), surpassing the efficacy of doxorubicin. Mechanistic investigations indicated that their cytotoxicity involved programmed cell death induction, as evidenced by increased protein expression of caspase‐7, cytochrome C, BAX, and p53, as well as reduced BCL‐2 protein levels, along with sub‐G1 cell cycle cessation via cyclin‐dependent kinase genes expression downregulation. All derivatives showed PARP1 inhibitory activity, with 5a–e, 8a, 13, 34, and 36, outperforming olaparib with sub‐nanomolar IC50 values. Molecular docking revealed that the derivatives docked well with PARP1, consistent with enzymatic inhibition data. Our findings support further optimization of these bis‐heterocyclic scaffolds as next‐generation anticancer agents and potent PARP1 inhibitors.
Source: ChemMedChem
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
Award: G1165803018
OpenAlex ID: W4410243646