Evaluation of Cancer-Preventive Activity and Structure–Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogs
3-Demethylubiquinone Q2 (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 analogs (3–14) are reported.
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 methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance.
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.
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.
Key Wordsapoptosis cancer prevention marine prenylated quinones nuclear factor structure–activity relationship
- 3-demethylubiquinone Q2
epidermal growth factor
fetal bovine serum
minimum essential medium
This work was supported in part by The Hormel Foundation and National Institutes of Health grants CA81064, CA77646, and CA88961. The Russian co-authors are grateful for financial support by the RFFI Grant no. 05-04-48246, Russian Federation President Grant no. 725.2003.4, Program of Presidium of RAS “Molecular and Cell Biology” Grant no. 05-I-05-005, and FEB Grant no. 05-III-A-05-129.
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