Evaluating Bis-Phenacyl Bromide-Based Bis-Heterocyclic Templates as Anticancer Prototypes and Potential PARP1 Inhibitors.

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.