title: Cancer chemopreventive potential of aromathecins and phenazines, novel natural product derivatives.
abstract: In the search for agents with cancer chemopreventive potential, 14-chloromethyl-12H-5,11a-diazadibenzo[b,h]fluoren-11-one (compound 1), originally synthesized as a potential topoisomerase I inhibitor, and 2,4-dibromo-1-hydroxyphenazine (compound 2), an analog of a substance found in the marine bacteria Streptomyces CNS284, were found to significantly enhance NADP(H):quinone oxidoreductase 1 (QR1), glutathione S-transferase (GST), and glutathione (GSH) levels in cell culture. However, following a short-term absorption study, analyses of livers from the treatment groups did not reveal a significant increase in QR1 or GST activity, or GSH levels. This was consistent with RT-PCR analyses of tissue samples. The compounds were absorbed, as judged by LC/MS analyses of serum and tissue samples, although levels were well below the concentrations required to mediate in vitro responses. Metabolites of compound 2 formed in vitro by human liver microzones were characterized using high resolution tandem mass spectrometry. In sum, the in vivo activity of these compounds appears to be diminished by low bioavailability, but this experimental approach indicates the importance of systematic biomarker investigation.
authors.affiliation: College of Pharmacy, University of Hawaii, Hilo, Hawaii 96720, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Marler
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: Maris A
authors.initials: MA
authors.lastname: Cinelli
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Morrell
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Lian
authors.initials: L
authors.lastname: Chen
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Richard
authors.initials: R
authors.lastname: Van Breemen
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010619:Phenazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D016588:Anticarcinogenic Agents; D001798:Blood Proteins; D005449:Fluorenes; D010619:Phenazines; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D005978:Glutathione