1. Cancer chemopreventive potential of aromathecins and phenazines, novel natural product derivatives.
- Author
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Marler L, Conda-Sheridan M, Cinelli MA, Morrell AE, Cushman M, Chen L, Huang K, Van Breemen R, and Pezzuto JM
- Subjects
- Animals, Anticarcinogenic Agents chemistry, Blood Proteins metabolism, Caco-2 Cells, Fluorenes chemistry, Glutathione metabolism, Glutathione Transferase metabolism, Humans, Intestinal Absorption drug effects, Liver Neoplasms, Experimental drug therapy, Liver Neoplasms, Experimental enzymology, Liver Neoplasms, Experimental metabolism, Male, Mice, Mice, Inbred BALB C, Microsomes, Liver drug effects, Microsomes, Liver metabolism, NAD(P)H Dehydrogenase (Quinone) metabolism, Phenazines chemistry, Protein Binding, Anticarcinogenic Agents pharmacology, Fluorenes pharmacology, Phenazines pharmacology
- 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.
- Published
- 2010