title: Synthesis of hybrid 4-deoxypodophyllotoxin-5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest.
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.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Guan
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Feng
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
authors.forename: Shi-Wu
authors.initials: SW
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Hui
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C000611971:4'-O-demethyl-4-deoxypodophyllotoxin-4'-yl 4-((6-(2-(5-fluorouracil-yl)acetamido)hexyl)amino)-4-oxobutanoate; D000970:Antineoplastic Agents; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; D011034:Podophyllotoxin
keywords: 5-Fluorouracil; Cell cycle arrest; Cell migration; Podophyllotoxin