title: Role of lipophilicity in the in vitro antitumour activity of a series of new mitosene compounds.
abstract: The antitumour activity of a series of mitosene compounds in various in vitro tumour models was evaluated in terms of physico-chemical parameters. Lipophilicity, measured as log P, seemed to be important for in vitro antitumour activity in three different cell lines. The in vitro activity of this series of mitosenes in an A204 and a L1210 cell line demonstrated a clear bilinear dependence on log P with optimal activity at log P values of 2.8 and 3.3 respectively. Compounds not able to be activated to bifunctional alkylating species did not fit into this correlation. Although mitosenes have to be activated reductively to alkylating species, no correlation was found between the half-wave reduction potential (E 1/2) and the in vitro activity. This lack of correlation may be caused by the relatively small range of E 1/2-values within this series of mitosene compounds. Our results indicate that penetration of the antitumour mitosenes into the cell and the site of activation is an important process that leads to antitumour activity and that within the range of compounds studied the structural variations are less important for bioreductive activation.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Maliepaard
authors.forename: N J
authors.initials: NJ
authors.lastname: de Mol
authors.forename: L H
authors.initials: LH
authors.lastname: Janssen
authors.forename: W
authors.initials: W
authors.lastname: van der Neut
authors.forename: W
authors.initials: W
authors.lastname: Verboom
authors.forename: D N
authors.initials: DN
authors.lastname: Reinhoudt
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy; D008563:Membrane Lipids / Q000378:metabolism; D016685:Mitomycin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008937:Mitomycins; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D008563:Membrane Lipids; D008937:Mitomycins; D016685:Mitomycin