2. Academic Validation
  3. Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives

Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives

  • Bioorg Med Chem Lett. 2022 Oct 15:74:128925. doi: 10.1016/j.bmcl.2022.128925.
Honglu Yin 1,  Yuepeng Chen 1,  Qiu Zhong 2,  Shilong Zheng 3,  Guangdi Wang 4,  Ling He 5
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China; Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: qzhong@xula.edu.
  • 3 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: szheng@xula.edu.
  • 4 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: gwang@xula.edu.
  • 5 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China; Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: heling2012@scu.edu.cn.
PMID: 35944852 DOI: 10.1016/j.bmcl.2022.128925
Abstract

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, β unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung Cancer cells, MDA-MB-231 breast Cancer cells, and Hela human cervical Cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 μM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 μM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 μM.

Keywords

1-oxa-4-azaspironenone derivatives; Antitumor activity; Cyclopropanation; Michael addition.

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