title: Synthesis and biological evaluation of conjugates of deoxypodophyllotoxin and 5-FU as inducer of caspase-3 and -7.
abstract: In order to generate compounds with superior antitumor activity and reduced toxicity, a series of conjugates of deoxypodophyllotoxin and 5-FU were synthesized by coupling 4'-demethyl-4-dexoypodophyllotoxin with N-(5-fluorouracil-N(1)-ly acetic)- amino acids (or 5-fluorouracil-N(1)-ly acetic acid). The cytotoxic activity of these compounds against four human cancer cell lines (HL-60, A-549, HeLa and SiHa) were evaluated, and results indicated that these compounds were more potent in terms of cytotoxicity than either parent compound DPT or anticancer drug VP-16 and 5-FU. In addition, we found that 14d induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells, and 14d activated caspase-3 and -7. These results suggested that caspase-mediated pathways are involved in 14d induced apoptosis.
authors.affiliation: School of Pharmacy & Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Jian-Fei
authors.initials: JF
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Hui
authors.forename: Yi-Lan
authors.initials: YL
authors.lastname: Ding
authors.forename: Shi-Wu
authors.initials: SW
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; C014451:deoxypodophyllotoxin; D053148:Caspase 3; D053179:Caspase 7; D011034:Podophyllotoxin; D005472:Fluorouracil