title: Design, synthesis, and evaluation of a water-soluble antofine analogue with high antiproliferative and antitumor activity.
abstract: New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.
authors.affiliation: College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Republic of Korea.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Kwon
authors.forename: Jayoung
authors.initials: J
authors.lastname: Song
authors.forename: Boeun
authors.initials: B
authors.lastname: Lee
authors.forename: Jinkyung
authors.initials: J
authors.lastname: In
authors.forename: Hohyun
authors.initials: H
authors.lastname: Song
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010618:Phenanthrolines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010618:Phenanthrolines; C473343:antofine; D014867:Water; D058570:TOR Serine-Threonine Kinases