Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation

  • Medchemcomm. 2019 Jan 23;10(3):413-420. doi: 10.1039/c8md00556g.
Xiaodong Ma  1  2 ,  Fang Fang  1  2 ,  Qiangqiang Tao  1 ,  Li Shen  3 ,  Guochen Zhong  1 ,  Tao Qiao  1 ,  Xiaoqing Lv  4 ,  Jiaming Li  1  2
Affiliations
  • 1. School of Pharmacy , Anhui University of Chinese Medicine , Hefei 230031 , China . Email: [email protected].
  • 2. Department of Medicinal Chemistry , Anhui Academy of Chinese Medicine , Hefei 230031 , China.
  • 3. Ocean College , Zhejiang University , Zhoushan , China.
  • 4. College of Medicine , Jiaxing University , Jiaxing 314001 , China . Email: [email protected].
PMID: 30996859 DOI: 10.1039/c8md00556g
Abstract

A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized via the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC50 values against PI3Kδ, along with low micromolar to submicromolar GI50 values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC50 = 6.3 nM) and anti-proliferative activity (GI50 = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, in vitro metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.