Design, synthesis, and biological evaluation of adenosine derivatives targeting DOT1L and HAT as anti-leukemia agents

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107771, Article 107771
• Main Authors: Sethy, Bidyadhar, Yu, Zih-Yao, Narwanti, Iin, Upadhyay, Richa, Lai, Mei-Jung, Lee, Sung-Bau, Liou, Jing-Ping
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia cancers; Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Adenosine derivative; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; DOT1L inhibitor; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - metabolism; Humans; Leukemia - drug therapy; Leukemia - pathology; Methyltransferases - antagonists & inhibitors; Methyltransferases - metabolism; Molecular Structure; Piperidine-4-ylmethyl motif; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107771

[Display omitted] •A series of adenosine derivatives were designed and synthesized as anti-leukemia agents.•All the synthetics possessed low to submicromolar DOT1L inhibitory activity.•Compound 12 exhibited potent DOT1L inhibitory activity and significantly reduced H3K79 dimethylation in cells.•Compound 15 displayed strong cellular inhibition in MLL-r and non-MLL-r cells with IC50 values in the 0.45 ∼ 1.66 μM.•Compound 15 hindered histone acetylation, induced remarkable DNA damage, and triggered apoptosis in leukemia cell lines. Disruptor of telomeric silencing 1-like (DOT1L) is a key hub in histone lysine methyltransferase and an attractive therapeutic target for treating hematological malignancies including acute myeloid leukemia (AML). In this study, we report the design and synthesis of a new series of adenosine derivatives as DOT1L inhibitors by accommodating a basic linker piperidine-4-ylmethyl motif to respective aryl-urea/benzimidazole scaffolds. The anti-DOT1L enzyme activity analysis demonstrated that compounds 8, 12, and 13 strongly suppressed DOT1L activity with IC50 values ranging from 0.125 to 0.408 µM among all the synthetics, and the structure–activity relationships were summarized. Moreover, compound 12 possessed relatively potent DOT1L inhibitory activity by significantly reduced histone H3 di-methylation at lysine 79 (H3K79me2) level in cells. Subsequently, all the synthetics were screened against various leukemia cell lines, indicating the DOT1L active adenosine derivatives exhibited low to moderate while compound 15 showed strong cellular inhibition despite its unsuccessful DOT1L inhibition. Therefore, acknowledging the distinctive potency of compound 15 against five different leukemia cell lines, including MLL-r (MV4-11) and non-MLL-r cell lines (HL-60, HH, K562, and KG-1), with IC50 values in the 0.45 ∼ 1.66 μM range and its mode of action was explored. Furthermore, compound 15 hindered histone acetylation, induced remarkable DNA damage, and triggered apoptosis. Importantly, normal T lymphocytes only showed moderate response to compound 15. These findings provide a basis for future studies on its potential application against AML.