Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Galectin-3 and Galectin-8 C-Terminal Domain Inhibitors

Haoming Zhang; Xiaoyu Wang; Yanjun Wan; Liheng Liu; Jie Zhou; Pingping Li; Bailing Xu

doi:10.1021/acsmedchemlett.3c00261

Discovery of N-Arylsulfonyl-Indole-2-Carboxamide Derivatives as Galectin-3 and Galectin-8 C-Terminal Domain Inhibitors

ACS Med Chem Lett. 2023 Aug 15;14(9):1257-1265. doi: 10.1021/acsmedchemlett.3c00261. eCollection 2023 Sep 14.

Authors

Haoming Zhang¹, Xiaoyu Wang¹, Yanjun Wan^{2

3

4}, Liheng Liu^{2

3

4}, Jie Zhou¹, Pingping Li^{2

3

4}, Bailing Xu¹

Affiliations

¹ Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
² State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
³ Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100050, China.
⁴ CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China.

PMID: 37736168
PMCID: PMC10510525 (available on 2024-09-14)
DOI: 10.1021/acsmedchemlett.3c00261

Abstract

Both galectin-3 and galectin-8 are involved in cell adhesion, migration, apoptosis, angiogenesis, and inflammatory processes by recognizing galactose-containing glycoproteins. Inhibiting galectin-3/8 activities is a potential treatment for cancer and tissue fibrosis. Herein, a series of novel N-arylsulfonyl-5-aryloxy-indole-2-carboxamide derivatives was disclosed as dual inhibitors toward galectin-3 and galectin-8 C-terminal domain with K_d values of low micromolar level (Cpd53, gal-3: K_d= 4.12 μM, gal-8C: K_d= 6.04 μM; Cpd57, gal-3: K_d= 12.8 μM, gal-8C: K_d= 2.06 μM), which are the most potent and selective noncarbohydrate-based inhibitors toward gal-3/8 isoforms to date. The molecular docking investigations suggested that the unique amino acids Arg144 in galectin-3 and Ser213 in galectin-8C could contribute to their potency and selectivity. The scratch wound assay demonstrated that Cpd53 and Cpd57 were able to inhibit the MRC-5 lung fibroblast cells migration as well. This class of inhibitors could serve as a new starting point for further discovering structurally distinct gal-3 and gal-8C inhibitors to be used in cancer and tissue fibrosis treatment.