title: Chirality of a 1,10-bisacetoxymitosene compound. Impact on reductive activation, DNA interstrand cross-linking and antitumour activity.
abstract: The absolute configuration at the C-1 position of a 1,10-bisacetoxymitosene (WV15) appears to be important for enzymatic reduction, DNA interstrand cross-linking and in vitro antitumour activity of this compound. DNA cross-linking by the (-)-(S)-enantiomer of WV15 upon reduction with sodium dithionite (Na2S2O4) was more efficient than cross-linking by the (+)-(R)-enantiomer. Also, following enzymatic two-electron reduction by DT-diaphorase or one-electron reduction by xanthine oxidase, (-)-(S)-WV15 was more efficient in DNA cross-linking than (+)-(R)-WV15. However, the difference in cross-linking efficiency was less than upon chemical reduction, and in the case of enzymatic reduction that higher amount of DNA cross-links formed by (-)-(S)-WV15 can be explained by more efficient enzymatic activation of this enantiomer as compared to (+)-(R)-WV15. The enantiomeric preference upon chemical reduction can be explained by a second chemical reduction of DNA-bound WV15, which presumably does not occur upon enzymatic reduction. (-)-(S)-WV15 appeared to be more active than its (+)-(R) counterpart in A204 and L1210 tumour cell lines, with (+)-(R)/(-)-(S) toxicity ratios as high as 200 and 68, respectively. In Chinese hamster V79 cell lines, toxicity of the enantiomers was measured under oxic and hypoxic conditions. The oxic/hypoxic toxicity ratios of (+)-(R)-and (-)-(S)-WV15 in the Chinese hamster V79 cell line were 5.5 and 2.4, respectively. These different oxic/hypoxic toxicity ratios may indicate that different reducing enzymes are involved in the activation of the enantiomers. Generally, in biological systems, different activities of (+)-(R)- and (-)-(S)-WV15 appear not to be caused by different intrinsic cross-linking capacities of the enantiomers, but by more efficient enzymatic activation of (-)-(S)-WV15, as compared to (+)-(R)-WV15. The (-)-(S)-enantiomer of WV15 appears to be more active both in in vitro tumour models and in DNA cross-linking assays, and therefore the absolute configuration of mitosenes is indicated to be important for the antitumour activity of these compounds.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Maliepaard
authors.forename: S E
authors.initials: SE
authors.lastname: Groot
authors.forename: N J
authors.initials: NJ
authors.lastname: de Mol
authors.forename: L H
authors.initials: LH
authors.lastname: Janssen
authors.forename: M
authors.initials: M
authors.lastname: Freriks
authors.forename: W
authors.initials: W
authors.lastname: Verboom
authors.forename: D N
authors.initials: DN
authors.lastname: Reinhoudt
authors.forename: M
authors.initials: M
authors.lastname: Stephens
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008937:Mitomycins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D012208:Rhabdomyosarcoma; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: C100960:1,10-bisacetoxymitosene WV15; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D008937:Mitomycins; D004247:DNA; D014969:Xanthine Oxidase; D008058:Dihydrolipoamide Dehydrogenase