Design, Synthesis, and Biological Evaluation of AnthraquinoneSulfonamide and Carboxamide Analogs: Cytotoxicity and PreliminaryHDAC-Modulating Effects

Abstract Anthraquinones are well-recognized anticancer scaffolds, but their systematic optimization within an HDAC-inspired pharmacophore framework remains limited. Since HDAC dysregulation is closely associated with cancer progression, chromatin remodeling, and cell-cycle control, applying this design strategy to anthraquinone scaffolds may provide a useful route toward new anticancer analogs. Herein, a focused series of anthraquinone sulfonamide and carboxamide analogs were designed using an extended cap-connecting unit (CU)–linker–terminal zinc-binding group (ZBG) concept. The anthraquinone core was employed as a cap-like scaffold, sulfonamide or carboxamide was employed as the CU, amino acid-derived fragments were employed as linkers, and methyl ester, carboxylic acid, or hydrazide groups were employed as terminal ZBG-like functionalities. Cytotoxicity screening identified sulfonamide hydrazides as the most active subgroup, with 4a showing potent activity against A549 and HeLa cells (IC50 = 5.18 and 6.36 μM, respectively). In contrast, 8d exhibited moderate cytotoxicity against HeLa cells (IC50 = 9.43 μM) and low toxicity toward Vero cells (IC50 > 100 μM). At 100 μM, preliminary single-concentration screening showed that 4a inhibited HDAC activity in the HeLa nuclear extract and HDAC2 by 16.46% and 14.59%, respectively, whereas 8d produced 64.56% and 38.08% inhibition, respectively. Cellular changes in Ac–H3 and p21 did not fully parallel these biochemical results. Both compounds induced cell-line-dependent apoptosis and cell-cycle perturbation. Exploratory docking predicted Zn2+ coordination by 8d in HDAC2, while in silico ADMET analysis suggested a more favorable physicochemical profile for 4a. Overall, 4a and 8d are identified as cytotoxic anthraquinone analogs with distinct, preliminary, and compound-dependent HDAC-modulating effects, providing a rationale for further mechanistic investigation.