CuI-mediated synthesis of 1-aryl-5,6,7-trimethoxybenzimidazoles as potent antitubulin agents

Cong-Min Peng; Shih-Wei Wang; Yi-Lin Hwang; Wen-Chun Sun; Li-Pin Chiu; Yi-Ting Liu; Yu-Wei Lai; Hsueh-Yun Lee

doi:10.1039/d3ra01927f

CuI-mediated synthesis of 1-aryl-5,6,7-trimethoxybenzimidazoles as potent antitubulin agents

RSC Adv. 2023 Apr 28;13(19):13169-13176. doi: 10.1039/d3ra01927f. eCollection 2023 Apr 24.

Authors

Cong-Min Peng¹, Shih-Wei Wang^{2

3

4}, Yi-Lin Hwang¹, Wen-Chun Sun^{2

5}, Li-Pin Chiu^{6

7}, Yi-Ting Liu¹, Yu-Wei Lai^{8

9}, Hsueh-Yun Lee^{1

10

11}

Affiliations

¹ School of Pharmacy, College of Pharmacy, Taipei Medical University Taipei Taiwan hyl@tmu.edu.tw.
² Institute of Biomedical Sciences, MacKay Medical College New Taipei City Taiwan.
³ Department of Medicine, MacKay Medical College New Taipei City Taiwan.
⁴ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University Kaohsiung Taiwan.
⁵ Division of Colon and Rectal Surgery, Department of Surgery, MacKay Memorial Hospital Taipei Taiwan.
⁶ Division of General Surgery, Taipei City Hospital Chushing Branch Taipei Taiwan.
⁷ General Education Center, University of Taipei Taipei Taiwan.
⁸ Division of Urology, Taipei City Hospital Renai Branch Taipei Taiwan.
⁹ Department of Urology, School of Medicine and Shu-Tien Urological Science Research Center, National Yang Ming Chiao Tung University Taipei Taiwan.
¹⁰ PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University Taipei Taiwan.
¹¹ TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei Taiwan.

Abstract

In situ CuI-mediated cyclization methodology helped yield benzimidazoles with different substitution manner, such as 1,2-diarylbenzimidazoles (4 and 5) and 1-arylbenzimidazoles (6-15). The result of structure-activity relationship (SAR) study confirmed the significance of the 5,6,7-trimethoxybenzimidazole moiety, and the representative derivatives (8-10) exhibited marked antiproliferative activity against A549, HCT-116, and PC-3 cells; in addition, they are able to inhibit the polymerization of tubulin. Among them, compound 10 inhibited the growth of A549, HCT-116, and PC-3 cells with a mean IC₅₀ value of 0.07 μM, and its IC₅₀ value of tubulin polymerization is 0.26 μM.