Structure-guided development of purine amide, hydroxamate, and amidoxime for the inhibition of non-small cell lung cancer

Meng-Ruo Huang; Yuan-Ling Hsu; Tzu-Chen Lin; Ting-Jen Cheng; Ling-Wei Li; Yu-Wei Tseng; Yu-Shu Chou; Jyung-Hurng Liu; Szu-Hua Pan; Jim-Min Fang; Chi-Huey Wong

doi:10.1016/j.ejmech.2019.07.054

Structure-guided development of purine amide, hydroxamate, and amidoxime for the inhibition of non-small cell lung cancer

Eur J Med Chem. 2019 Nov 1:181:111551. doi: 10.1016/j.ejmech.2019.07.054. Epub 2019 Jul 22.

Authors

Affiliations

¹ Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan.
² Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
³ The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
⁴ Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; Department of Life Sciences, National Chung Hsing University, Taichung, 402, Taiwan; Agricultural Biotechnology Center, National Chung Hsing University, Taichung, 402, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan. Electronic address: jhliu@nchu.edu.tw.
⁵ Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 100, Taiwan; Doctoral Degree Program of Translational Medicine, National Taiwan University, Taipei, 100, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, 100, Taiwan. Electronic address: shpan@ntu.edu.tw.
⁶ Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan; The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. Electronic address: jmfang@ntu.edu.tw.

PMID: 31376567
DOI: 10.1016/j.ejmech.2019.07.054

Abstract

An 8-oxopurine-6-carboxamide compound (1a) was previously identified as an inhibitor of non-small cell lung cancer (NSCLC). In this study, more than 30 purine-6-carboxamide derivatives with variations at the C2, N7, C8, and N9 positions were synthesized to investigate the structure-activity relationship as a basis for the construction of an advanced pharmacophore model. This model suggests that purine-6-hydroxamate and purine-6-amidoxime analogs could form more hydrogen bonds with a target protein to enhance the inhibitory activities against H1975 cells. Among the series of analogs, hydroxamate 17 and amidoxime 19a exhibited excellent potency against H1975 cells (IC₅₀ < 1.5 μM) and other lung cancer cells with either wild-type or mutated epidermal growth factor receptor (EGFR). Mouse experiments indicated that compounds 17 and 19a were efficient anticancer agents with no appreciable toxicity. The mechanisms of action for the induction of cell apoptosis were determined to involve microtubule fragmentation and p53-mediated signaling pathways.

Keywords: Amidoxime; Hydroxamate; Lung cancer; Microtubule; Purine amide.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Oximes / chemistry
Oximes / pharmacology*
Purines / chemistry
Purines / pharmacology*
Structure-Activity Relationship

Substances

Amides
Antineoplastic Agents
Hydroxamic Acids
Oximes
Purines
amidoxime
purine