Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors

  • Bioorg Med Chem. 2015 May 1;23(9):1982-93. doi: 10.1016/j.bmc.2015.03.022.
Sida Shen  1 ,  Xingyu Xu  1 ,  Zhulong Liu  1 ,  Junhua Liu  2 ,  Lihong Hu  3
Affiliations
  • 1. Shanghai Research Center for the Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China.
  • 2. Shanghai Research Center for the Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China. Electronic address: [email protected].
  • 3. Shanghai Research Center for the Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, PR China. Electronic address: [email protected].
PMID: 25819335 DOI: 10.1016/j.bmc.2015.03.022
Abstract

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC₅₀: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.

Keywords
Acetyl-11-keto-β-boswellic acid; Structure–activity relationship; Synthesis; VEGFR-2.