Synthesis and evaluation of potent (iso)ellipticine-based inhibitors of MYLK4 accessed via expeditious synthesis from isoquinolin-5-ol

Szu Lee; Min-Wu Chao; Yi-Wen Wu; Chia-Min Hsu; Tony Eight Lin; Kai-Cheng Hsu; Shiow-Lin Pan; Hsueh-Yun Lee

doi:10.1039/d3ra06600b

Synthesis and evaluation of potent (iso)ellipticine-based inhibitors of MYLK4 accessed via expeditious synthesis from isoquinolin-5-ol

RSC Adv. 2023 Oct 30;13(45):31595-31601. doi: 10.1039/d3ra06600b. eCollection 2023 Oct 26.

Authors

Szu Lee¹, Min-Wu Chao^{2

3

4}, Yi-Wen Wu⁵, Chia-Min Hsu⁵, Tony Eight Lin^{5

6}, Kai-Cheng Hsu^{5

6

7

8

9}, Shiow-Lin Pan^{5

6

7

8

9}, Hsueh-Yun Lee^{1

9

10}

Affiliations

¹ School of Pharmacy, College of Pharmacy, Taipei Medical University Taiwan hyl@tmu.edu.tw +886-2-7361661.
² School of Medicine, College of Medicine, National Sun Yat-sen University Kaohsiung Taiwan.
³ Institute of Biopharmaceutical Sciences, College of Medicine, National Sun Yat-sen University Kaohsiung Taiwan.
⁴ The Doctoral Program of Clinical and Experimental Medicine, College of Medicine, National Sun Yat-sen University Kaohsiung Taiwan.
⁵ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei Taiwan.
⁶ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei Taiwan.
⁷ TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei Taiwan.
⁸ TMU Research Center for Drug Discovery, Taipei Medical University Taipei Taiwan.
⁹ PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University Taipei Taiwan.
¹⁰ Master Program in Clinical Genomics and Proteomics, College of Pharmacy, Taipei Medical University Taipei Taiwan.

Abstract

The K₂S₂O₈-mediated generation of p-iminoquinone contributed to the regioselective substitution of isoquinolin-5,8-dione. This hydroxyl group-guided substitution was also applied to selected heterocycles and addressed the regioselectivity issue of quinones. This study has provided an expeditious pathway from isoquinolin-5-ol (5) to ellipticine (1) and isoellipticine (2), which benefits the comprehensive comparison of their activity. Compounds 1 and 2 displayed marked MYLK4 inhibitory activity with IC₅₀ values of 7.1 and 6.1 nM, respectively. In the cellular activity of AML cells (MV-4-11 and MOLM-13), compound 1 showed better AML activity than compound 2.