Badal, Simone A.; Gallimore, Winklett A.; Huang, G.; George, T; Delgoda, Rupika.
Author Affiliation, Ana.
Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata
Organic and Medicinal Chemistry Letters
Date of Publication
Background: Extracts from the marine algae Cymopolia barbata have previously shown promising pharmacological activity including antifungal, antitumor, antimicrobial, and antimutagenic properties. Even though extracts have demonstrated such bioactivity, isolated ingredients responsible for such bioactivity remain unspecified. In this study, we describe chemical characterization and evaluations of biological activity of prenylated bromohydroquinones (PBQ) isolated from the marine algae C. barbata for their cytotoxic and chemopreventive potential.Methods: The impact of PBQs on the viability of cell lines (MCF-7, HT29, HepG, and CCD18 Co) was evaluated using the MTS assay. In addition, their inhibitory impact on the activities of heterologously expressed cytochrome P450 (CYP) enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4) was evaluated using a fluorescent assay.Results: 7-Hydroxycymopochromanone (PBQ1) and 7-hydroxycymopolone (PBQ2) were isolated using liquid and column chromatography, identified using 1 H and 13 C NMR spectra and compared with the spectra of previously isolated PBQs. PBQ2 selectively impacted the viability of HT29, colon cancer cells with similar potency to the known chemotherapeutic drug, fluorouracil (IC50, 19.82 ± 0.46 µM compared to 23.50 ± 1.12 µM, respectively) with impact toward normal colon cells also being comparable (55.65 ± 3.28 compared to 55.51 ± 3.71 µM, respectively), while PBQ1 had no impact on these cells. Both PBQs had potent inhibition against the activities of CYP1A1 and CYP1B1, the latter which is known to be a universal marker for cancer and a target for drug discovery. Inhibitors of CYP1 enzymes by virtue of the prevention of activation of carcinogens such as benzo-a-pyrene have drawn attention as potential chemopreventors. PBQ2 potently inhibited the activity of CYP1B1 (IC50 0.14 ± 0.04 µM), while both PBQ1 and PBQ2 potently inhibited the activity of CYP1A1 (IC50s of 0.39 ± 0.05 µM and 0.93 ± 0.26 µM, respectively). Further characterizations showed partial noncompetitive enzyme kinetics for PBQ2 with CYP1B1 with a Ki of 4.7 × 10–3 ± 5.1 × 10–4 µM and uncompetitive kinetics with CYP1A1 (Ki = 0.84 ± 0.07 µM); while PBQ1 displayed partial non competitive enzyme kinetics with CYP1A1 (Ki of 3.07 ± 0.69 µM), noncompetitive kinetics with CYP1A2 (Ki = 9.16 ± 4.68 µM) and uncompetitive kinetics with CYP1B1 (Ki = 0.26 ± 0.03 µM) .Conclusions: We report for the first time, two isolated ingredients from C. barbata, PBQ1 and PBQ2, that show potential as valuable chemotherapeutic compounds. A hydroxyl moiety resident in PBQ2 appears to be critical for selectivity and potency against the cancer colon cells, HT29, in comparison to the three other malignant cell lines studied. PBQs also show potency against the activities of CYP1 enzyme which may be a lead in chemoprevention. This study, the first on isolates from these marine algae, exemplifies the value of searching within nature for unique structural motifs that can display multiple biological activities.....