Evaluation of Cancer-Preventive Activity and Structure–Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogs

Abstract

Purpose-3-Demethylubiquinone Q 2 (1) was isolated from the ascidian Aplidium glabrum. The cancer preventive properties and the structure-activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogues (3-14) are reported.Methods-Compounds 3-14, having one or several di-or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer preventive properties of compounds 1 and 3-14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the MTS assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance.Results-All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1 and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution.Conclusions-Quinones 1 and 3-14 demonstrated cancer preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.Keywords marine prenylated quinones; cancer prevention; apoptosis; nuclear factor; structure-activity relationship ABBREVIATIONS 3-demethylubiquinone Q2. 2,3-dimethoxy-5-(3′,7′-dimethyl-octa-2′(E),6′-dienyl)- [1,4] benzoquinone (1); EGF, epidermal growth factor; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; FBS, fetal bovine serum; MEM, minimum essential medium

The inhibition of TNF-α-induced NF-κB activation by marine natural products

“…The high hit rate observed for chordate-derived extracts is novel and highly promising, as the only natural products isolated from this phylum and reported as NF-B inhibitors to date is the quinone 3-demethylubiquinone Q 2 from the ascidian Aplidium glabrum [84]. (2) isolated from the echinoderm Comanthus parvicirrus and the isomalabaricanes stellettin A (3) and stellettin B (4) isolated from the sponge Rhabdastrella globostellata possess lactone rings with -unsaturated carbonyl groups which may be responsible for the latter's interferences with IKK and with the binding of NF-B to DNA as described previously for other NF-B-inhibiting natural products [21].…”

Synthesis and NMR Structure Determination of New Linear Geranylphenols by Direct Geranylation of Activated Phenols

“…int.). 1 H, 13 C, 13 C DEPT-135, sel. gs1D 1 H NOESY, gs 2D HSQC and gs 2D HMBC spectra were recorded in CDCl 3 solutions and are referenced to the residual peaks of CHCl 3 at δ = 7.26 ppm and δ = 77.0 ppm for 1 H and 13 C, respectively, on a Bruker Avance 400 Digital NMR spectrometer, operating at 400.1 MHz for 1H and 100.6 MHz for 13 C. For selective 1D NOESY experiment the selnogp.3 with Z-PFG pulse program was used, obtained from Bruker Library and optimizedparameter at ns = 32, ds = 4, d1 = 2.0sec, TD = 16k, sp2 = 73.0dB, p12 = 80msec, d8 = 600ms, and gradient ratios: gpz3 = 40, gpz4 = -40.…”

“…Fraction I: compound 15 as a yellow oil (0.09 g, 2.5%). 1 H NMR: 6.81-6.74 (m, 3H, H-3, H-4 and H-5); 5.72 (s, 1H, OH); 5.37 (t, J = 7,2Hz, 1H, H-2'); 5.13 (t, J = 6.6Hz, 1H, H-6'); 3.90 (s, 3H, OCH 3 ); 3.39 (d, J = 7.2Hz, 2H, H-1'); 2.14-2.11 (m, 2H, H-5'); 2.09-2.05 (m, 2H, H-4'); 1.74 (s, 3H, CH 3 -C3'); 1.70 (s, 3H, H-8'); 1.62 (s, 3H, CH 3 -C7'); 13 (E)-4-(3,7-dimethylocta-2,6-dienyl)benzene-1,3-diol 18 To a solution of resorcinol (1.00 g, 9.1 mmol) and BF 3 . OEt 2 (1.29 g, 9.1 mmol) in freshly distilled 1,4-dioxane (5 mL) was added dropwise, with stirring at room temperature and under a N 2 atmosphere, a solution of geraniol (2.80 g, 18.1 mmol) in 1,4-dioxane (5 mL).…”

“…Then, the ethereal layer was washed with 5% NaHCO 3 (30 mL), water (2 x 20 mL), dried over Na 2 SO 4 , filtered and the solvent was evaporated under reduced pressure. The crude was redissolved in CH 2 Cl 2 (5 mL) and the mixture was subjected to silica gel flash column chromatography with petroleum ether/EtOAc mixtures of increasing polarity (19.8:0.2→0.2:19.8) as the mobile phase to afford the compound 18 as a viscous yellow oil (0.268 g, 11.9%); 1 H NMR: 6.92 (d, J = 8.8Hz, 1H, H-5); 6.37 (d, J = 2.4Hz, 1H, H-2); 6.36 (dd, J = 2.4 and 8.8Hz, 1H, H-6); 5.30 (t, J = 7.0Hz, 1H, H-2'); 5.09 (t, J = 6.1Hz, 1H, H-6'); 3.27 (d, J = 7.0Hz, 2H, H-1'); 2.12-2.09 (m, 2H, H-5'); 2.08-2.06 (m, 2H, H-4'); 1.72 (s, 3H, CH 3 -C3'); 1.69 (s, 3H, H-8'); 1.60 (s, 3H, CH 3 -C7'); 13 OEt 2 (1.3 g, 9.1 mmol) in freshly distilled 1,4-dioxane (5 mL) was added dropwise, with stirring at room temperature and under a N 2 atmosphere, a solution of geraniol (1.4 g, 9.1 mmol) in 1,4-dioxane (5 mL). After the addition was complete, the stirring was continued overnight.…”

“…All the compounds tested were able to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-KB activity, and to inhibit p53 activity [13]. On the other hand, the geranylorcinol derivatives 4 and 5 (figure 1) showed antimicrobial and antifungal activities [14][15].…”