Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on aromatic rings

  • Bioorg Med Chem Lett. 2017 Sep 1;27(17):4199-4203. doi: 10.1016/j.bmcl.2017.06.070.
Satoshi Yamauchi  1 ,  Tuti Wukirsari  2 ,  Yoshiaki Ochi  2 ,  Hisashi Nishiwaki  2 ,  Kosuke Nishi  2 ,  Takuya Sugahara  3 ,  Koichi Akiyama  4 ,  Taro Kishida  3
Affiliations
  • 1. Graduate School of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan; South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan. Electronic address: [email protected].
  • 2. Graduate School of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
  • 3. Graduate School of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan; South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan.
  • 4. Advanced Research Support Center (ADRES), Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
PMID: 28754364 DOI: 10.1016/j.bmcl.2017.06.070
Abstract

The new lignano-9,9'-lactones (α,β-dibenzyl-γ-butyrolactone Lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC50=12μM), however, it was inactive against HeLa cells (EC50>100μM). The synthesized (3,4-dichloro, 2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the lignano-9,9'-lactone structures showed the EC50 values of 10μM and 9.4μM against HL-60 cells, respectively. Against HeLa cells, the EC50 value of the derivative 66 was 27μM. By comparing the activities with the corresponding 9,9'-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold difference.

Keywords
Arctigenin; Lignan; Lignano-9,9′-lactone; Matairesinol; α,β-Dibenzyl-γ-butyrolactone; γ-Butyrolactone.