Abstract
Several diterpenes with the labdane skeleton show biological activity, including antiproliferative effects. Most of the research work on bioactive labdanes has been carried out on naturally occurring diterpenes and semisynthetic derivatives, but much less is known on the effects of diterpene dimers. The aim of the present work was to synthesize dimeric diterpenes from the labdane imbricatolic acid using esters, ethers and the triazole ring as linkers. Some 18 new derivatives were prepared and the compounds were evaluated for antiproliferative activity on human normal fibroblasts (MRC-5) and the following human tumor cell lines: AGS, SK-MES-1, J82 and HL-60. The diethers 8–10, differing in the number of CH2 units in the linker, presented better antiproliferative activity with a maximum effect for the derivative 9. The best antiproliferative effect against HL-60 cells was found for compounds 3 and 17, with IC50 values of 22.3 and 23.2 µM, lower than that found for the reference compound etoposide (2.23 µM). The compounds 9, 17 and 11 were the most active derivatives towards AGS cells with IC50 values of 17.8, 23.4 and 26.1 µM. A free carboxylic acid function seems relevant for the effect as several of the compounds showed less antiproliferative effect after methylation.
Highlights
Natural product monomers occur in all living organisms and many can form polymeric structures, including rubber, cellulose or lignin
This paper describes the synthesis of some new dimeric diterpenes including esters, ethers and dimers fused by triazole rings, starting from the naturally occurring labdane imbricatolic acid
The diterpene imbricatolic acid, used as starting compound for the synthesis was isolated from the resin of Araucaria araucana
Summary
Natural product monomers occur in all living organisms and many can form polymeric structures, including rubber, cellulose or lignin. Less common are dimeric compounds formed by coupling two units by C-C, ester, ether, C-N or N-N bonds. It has been reported that dimeric compounds can be employed as potential anticancer agents because they might interact with two different binding sites on a receptor or on two separate monomers of a dimeric protein [1]. It has been observed that dimers maintained the activity shown by its monomer, but could increase it. The dimer montamine from Centaurea montana presented two times higher activity on in vitro colon cancer than its monomer [2]. Monomeric ergolines presented weak antiplasmodial effect, while dimerized ergoline derivatives, prepared using different aliphatic or arylalkyl spacers, showed significantly increased activity [3]
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