title: In vivo activity and hydrophobicity of cytostatic aziridinyl quinones.
abstract: For a series of 3,6-disubstituted bisaziridinylbenzoquinones the in vivo and in vitro activities against murine tumors, as well as the in vivo toxicity, are analyzed. Properties describing biochemical and physicochemical reactions are also incorporated in the analyses. The important 1-octanol/water partition coefficients were determined, using a fast variation of the shake flask method. New pi'-values were calculated for the substituents in this series. These quinone pi'-values deviate strongly from the standard pi-values, especially for hydrogen-bonding substituents. To discriminate between the toxic and therapeutic activity of the compounds, principal components and partial least squares analyses were applied. Evidence is presented for selective antitumor action of the investigated compounds. The L1210 clonogenic assay only seems to relate to the general cytotoxicity and has no predictive value for in vivo activity for these compounds. The activity is correlated to the hydrophobicity of the quinones. The toxicity correlates with the ease of reduction, contrary to the hypothesis of bioreductive activation as a mechanism for selectivity.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiteit Utrecht, The Netherlands.
authors.forename: E E
authors.initials: EE
authors.lastname: Moret
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: H W
authors.initials: HW
authors.lastname: Hilbers
authors.forename: J P
authors.initials: JP
authors.lastname: Tollenaere
authors.forename: L H
authors.initials: LH
authors.lastname: Janssen
authors.forename: J J
authors.initials: JJ
authors.lastname: Holthuis
authors.forename: R J
authors.initials: RJ
authors.lastname: Driebergen
authors.forename: W
authors.initials: W
authors.lastname: Verboom
authors.forename: D N
authors.initials: DN
authors.lastname: Reinhoudt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000473:pathology; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones