Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

Abstract

The semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies

“…was ester ≥ alcohol > acid, which is a trend similar to that of C19 callitrisic-derivative series. 22 Previous reports on the antiproliferative activity of sugiol β-amino alcohols analogues (6a, Figure 1), 14 provided similar cytotoxicity results against A2780, WiDr and SW1573 cancer cells after 48 h of exposure using the sulforhodamine B (SRB) assay. 14 An important difference in the β-amino alcohols analogues is the presence of a gem-dimethyl group at C4 in contrast with the C18-functionalized position in the current study.…”

“…Most of the compounds were active (GI50 < 25 µΜ) in the solid tumor cells with higher activity than the parent dehydroabietic acid (2) from previous results. 22 The target molecule, (+)-liquiditerpenoic acid (7, Compound 9 was also more potent against T-47D and WiDr cell lines than the standard of care drug, cisplatin.…”

Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues

“…The anticancer drugs cisplatin and etoposide were used for reference. Most of the molecules were active (GI50 < 25 μM) in the solid tumor cells with higher activity than parent ferruginol (1) and sugiol (2) as reported by Li et al [25] for A549 cell line and compounds 10-12 better than the starting methyl callitrisate (7) comparing with previous results [26]. The target molecule, (+)-4-epi-liquiditerpenoic acid (8a), showed better activity than sugiol (2) for the A549 cell line.…”

Secondary Metabolites from Pterocaulon alopecuroides and their Antiproliferative Activities

“…Compounds 1-5 were evaluated for antiproliferative activity using the protocol of the National Cancer Institute (NCI) of the USA with minor modifications. [3][4][5] Cells were seeded onto 96-well plates at cell densities of 2,500 (A549, HBL-100, HeLa and SW1573) or 5,000 (T-47D and WiDr) cells per well, depending on their doubling times. The results, expressed as GI 50 (50% growth inhibition) values after 48 h of drug exposure, were calculated according to NCI formulas.…”

“…• Phytochemical investigation of the ethanolic extract of the aerial parts of Pterocaulon alopecuroides (Asteraceae) afforded the compounds 7-(2,3-dihydroxy-3-methylbutoxy)-6-methoxycoumarin (1), 5,6-methylenedioxy-7-(2,3-dihydroxy-3-methylbutoxy) coumarin (2), Dihydrokaempferol (3), 5,7,4´-trihydroxy-6-(α,α-dimethylallyl)dihydroflavonol (4) and 5,4´-dihydroxy-7-(γ,γ-dimethylallyloxy)dihydroflavonol (5). All isolates were evaluated for their antiproliferative activities on a panel of six human tumor cell lines.…”