Synthesis of hybrid 4-deoxypodophyllotoxin-5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest

  • Bioorg Med Chem Lett. 2016 Mar 15;26(6):1561-1566. doi: 10.1016/j.bmcl.2016.02.013.
Xiao-Wen Guan  1 ,  Xiao-Hui Xu  1 ,  Shi-Liang Feng  1 ,  Zhen-Bo Tang  1 ,  Shi-Wu Chen  2 ,  Ling Hui  3
Affiliations
  • 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
  • 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
  • 3. Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China; Key Laboratory of Stem Cells and Gene Drug of Gansu Province, General Hospital of Lanzhou Military Command, Lanzhou 730050, China.
PMID: 26873416 DOI: 10.1016/j.bmcl.2016.02.013
Abstract

A series of deoxypodophyllotoxin-5-fluorouracil hybrid compounds were synthesized, and their cytotoxic activity was evaluated using four human Cancer cell lines (HeLa, A549, HCT-8, and HepG2) and the human normal cell line WI-38. The synthesized compounds exhibited greater cytotoxic activity in tumor cells and reduced toxicity in the normal cell line compared with the Anticancer drug VP-16 and 5-FU. Additionally, the most potent of these compounds-4'-O-demethyl-4-deoxypodophyllotoxin-4'-yl 4-((6-(2-(5-fluorouracil-yl) acetamido) hexyl) amino)-4-oxobutanoate (compound 22)-induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells. Furthermore, compound 22 may inhibited the migration of A549 cells via down-regulation of MMP-9 and up-regulation of TIMP-1.

Keywords
5-Fluorouracil; Cell cycle arrest; Cell migration; Podophyllotoxin.