Novel diosgenin–amino acid–benzoic acid mustard trihybrids exert antitumor effects via cell cycle arrest and apoptosis

• Published in: The Journal of steroid biochemistry and molecular biology 2022-02, Vol.216, p.106038-106038, Article 106038
• Main Authors: Wang, Wenbao, Li, Chuan, Chen, Zhe, Zhang, Jinling, Ma, Liwei, Tian, Yanzhao, Ma, Yukun, Guo, Lina, Wang, Xiaoli, Ye, Jin, Wang, Xiaobo
• Format: Article
• Language: English
• Subjects: A549 Cells; Amino acid; Amino acids; Amino Acids - chemistry; Amino Acids - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Benzoic acid; Benzoic Acid - chemistry; Benzoic Acid - pharmacology; Benzoic acid mustard; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemistry, Pharmaceutical; Cholecystokinin; Cytotoxicity; Depolarization; Diosgenin; Diosgenin - chemistry; Diosgenin - pharmacology; HCT116 Cells; Hep G2 Cells; Humans; MCF-7 Cells; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mustard Plant - chemistry; Reactive oxygen species; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Trihybrid; Tumor cell lines; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Zebrafish
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2021.106038

[Display omitted] •Fourteen novel diosgenin–amino acid–benzoic acid mustard trihybrids were designed and synthesized.•12e showed IC50 = 6.96 μM for human T24 bladder cancer cells and low toxicity against normal GES-1 cells.•12e induced G2/M cell cycle arrest and apoptosis in T24 cells.•Intrinsic and extrinsic apoptotic pathways involved in 12e-induced apoptosis in T24 cells.•12e inhibited T24 cell proliferation in an in vivo zebrafish xenograft model. In discovering new powerful antitumor agents, two series of novel diosgenin–amino acid–benzoic acid mustard trihybrids (7a–7 g and 12a–12 g) were designed and synthesized. The antiproliferative activities were tested against five human tumor cell lines and one normal cell line using CCK-8 assays. Among the trihybrids, 12e was the most promising compound, which inhibited T24 cells with IC50 value of 6.96 μM, and was stronger than its parent compound diosgenin (IC50 = 32.33 μM). In addition, 12e had weak cytotoxicity on the normal GES-1 cell line (IC50 = 213.74 μM). Moreover, 12e could cause G2/M cell cycle arrest, increase the percentage of apoptosis, induce mitochondrial depolarization, and promote reactive oxygen species generation in T24 cells. Further studies on antitumor mechanism demonstrated that 12e triggered the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways. More importantly, 12e could inhibit T24 cell proliferation in an in vivo zebrafish xenograft model. Therefore, 12e, as a novel trihybrid with potent cytotoxicity, might be applied as a promising skeleton for antitumor agents, which deserved further optimization.