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

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

  • Bioorg Chem. 2024 Sep 6:153:107771. doi: 10.1016/j.bioorg.2024.107771.
Bidyadhar Sethy 1 Zih-Yao Yu 2 Iin Narwanti 3 Richa Upadhyay 4 Mei-Jung Lai 5 Sung-Bau Lee 6 Jing-Ping Liou 7
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia.
  • 4 International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taiwan.
  • 5 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 6 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: sbl@tmu.edu.tw.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: jpl@tmu.edu.tw.
Abstract

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.

Keywords

Acute myeloid leukemia cancers; Adenosine derivative; DOT1L inhibitor; Piperidine-4-ylmethyl motif.

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