Semi-synthetic labdane compounds and their cytotoxicity against cancer cell Lines

Abstract

Chemical modifications of labda-7,12(E),14-triene-17-oic acid (14) isolated from the stem bark of Croton oblongifolius Roxb. were performed in two pathways : (1) transformation of the carboxyl group at C(17) position to its derivatives (2) conversion of 14 into (+)-limonidilactone (33), labdane diterpene bearing γ-butenolide and δ-lactone system. (+)-Limonidilactone was successfully synthesized in 22.3% overall yield by utilizing a four-step sequence reactions entailing : (i) epoxidation with m-CPBA and successive oxidation with H₅IO₆ ; (ii) further oxidation with Pb(OAc)₄ in the presence of BF₃.Oet₂ ; (iii) Wittig reaction and (iv) acidic hydrolysis yielded 33. Compound 14 and the modified labdanes were evaluated against five human cancer cell lines as well as tested for biological activity on Na⁺, K⁺-ATPase assay. Among labdane diterpenes tested, 12,17-dihydroxylabda-7,13-(E)-diene (54) showed a significant cytotoxic activity, exhibiting IC₅₀ value of 0.6 μg/mL against gastric carcinoma cell lines and labda-7,12(E),14-triene-17-ol (13) and compound 14 showed strong inhibitory activity on Na⁺, K⁺-ATPase assay (IC₅₀ values 9.0 x 10⁻⁵ and 5.0 x 10⁻⁵, respectively).