2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 3-substituted imidazo[1,2-a]pyridine and quinazolin-4(3H)-one derivatives as PI3Kα inhibitors

Design, synthesis, and biological evaluation of novel 3-substituted imidazo[1,2-a]pyridine and quinazolin-4(3H)-one derivatives as PI3Kα inhibitors

  • Eur J Med Chem. 2017 Oct 20:139:95-106. doi: 10.1016/j.ejmech.2017.07.074.
Yan-Hua Fan 1,  Wei Li 2,  Dan-Dan Liu 2,  Meng-Xuan Bai 2,  Hong-Rui Song 2,  Yong-Nan Xu 2,  SangKook Lee 3,  Zhi-Peng Zhou 1,  Jian Wang 2,  Huai-Wei Ding 4
Affiliations

Affiliations

  • 1 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: dinghuaiwei627@163.com.
PMID: 28800461 DOI: 10.1016/j.ejmech.2017.07.074
Abstract

Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of Cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of Cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five Cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kα distinguished from Other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kα Inhibitor and could be considered as a potential candidate for the development of Anticancer agents.

Keywords

Anticancer agents; Imidazo[1,2-a]pyridine; PIK3CA gene; Phosphatidylinositol 3-kinase; Quinazolin-4(3H)-one.

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