Cancer preventive agents 11. Novel analogs of dimethyl dicarboxylate biphenyl as potent cancer chemopreventive agents(†).

Abstract

CONTEXT:

Dimethyl dicarboxylate biphenyl (DDB) is a clinically used hepatoprotectant and has also been found to have chemopreventive activity.

MATERIALS AND METHODS:

Sixteen novel analogs (5-20) were designed, synthesized, and evaluated for their cancer preventive activity. The 2,2'-bismethyl ester (5-18) and ether (19, 20) DDB analogs were synthesized by insertion of various linear alkyl, short fatty acid, polar, and aromatic groups. All synthesized analogs were evaluated in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein Barr virus early antigen (EBA-EA) activation assay. Three of the most potent compounds were also tested for inhibitory effects on skin tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.

RESULTS:

Compound 19 with bisprenyl ethers had the most significant cancer preventive activity (100% inhibition of activation at 1 × 10(3) mol ratio/TPA, 78.4%, 49.7%, and 10.9% inhibition at 5 × 10(2), 1 × 10(2), 1 × 10 mol ratio/TPA, respectively) in vitro. Compound 19 also exhibited a remarkable inhibitory effect on skin tumor promotion in the in vivo two-stage mouse-skin carcinogenesis test.

DISCUSSION AND CONCLUSIONS:

Thus, DDB analog 19 could be a valuable candidate as a cancer preventive agent or as a lead for the development of new antitumor promoter drugs.

• Authors: Hsin-Yi Hung, Kyoko Nakagawa-Goto, Harukuni Tokuda, Akira Iida, Nobutaka Suzuki, Susan L Morris-Natschke, Kuo-Hsiung Lee
• Journal: Pharmaceutical biology (Pharm Biol) Vol. 50 Issue 1 Pg. 18-24 (Jan 2012) ISSN: 1744-5116 [Electronic] England
• PMID: 22196579 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anticarcinogenic Agents
• Antigens, Viral
• Dioxoles
• Epstein-Barr virus early antigen
• 9,10-Dimethyl-1,2-benzanthracene
• 7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Animals
• Anticarcinogenic Agents (chemical synthesis, chemistry, pharmacology)
• Antigens, Viral (metabolism)
• Dioxoles (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred ICR
• Skin Neoplasms (prevention & control)
• Tetradecanoylphorbol Acetate (pharmacology)