Title:Synthesis of Oleanolic Acid Analogues and Their Cytotoxic Effects on 3T3 Cell Line
Volume: 14
Issue: 6
Author(s): Salih Tuncay, Halil Senol, Eray Metin Guler, Nuket Ocal *, Hasan Secen, Abdurrahim Kocyigit and Gulacti Topcu*
Affiliation:
- Department of Chemistry, Faculty of Art and Sciences, Yildiz Technical University, 34220, Esenler, Istanbul,Turkey
- Department of Pharmacognosy & Phytochemistry, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Fatih, Istanbul,Turkey
Keywords:
Triterpenoids, oleanolic acid, spectral analysis, cytotoxicity, erythrodiol, anti-proliferative.
Abstract: Background: Oleanolic acid (OA) is a known natural compound with many important
biological activities. Thirteen oleanolic acid derivatives linked at C-3 and C-28 were synthesized
and their structures were confirmed by 1H- and 13C NMR and mass spectral analyses. Among
them, compounds 4, 6, 8-10, 12, 13 were synthesized for the first time. They were evaluated for
their cytotoxic activity. They showed proliferative effect at low concentrations while cytotoxic effect
was observed at high concentrations in a dose dependent manner.
Methods: We have first synthesized compounds 1 and 2 from the reaction of methyl iodide and
OA. Compound 1 was reduced with LiAlH4 to give compound 3, and compound 2 gave compound
9 with MOMBr as a new compound. The compound 10 was then obtained from the reduction of
compound 9 with LiAlH4 as a new oleanolic acid derivative. A diol derivative 11 was synthesized
from OA and LiAlH4 at the room temperature. Compound 4 was obtained from the reaction of
compound 3 with CBr4 as a new analogue of OA, and the reduction of compound 4 afforded compound
5 as a known product. In addition, we synthesized compounds 6-8 from compound 3 using
MsCl, MeI and p-nitrobenzoyl chloride, respectively, in good yields. Compounds 6 and 8 are new
analogues of OA. The new compounds 12 and 13 were also synthesized starting from OA using
with MOMBr and TBDMSiCl as the reagents. The all synthesized compounds were purified by
using column chromatography and/or crystallization.
Results: In the present study, thirteen OA derivatives linked at C-28 and (or) C-3 were synthesized
and evaluated for their cytotoxic activity on 3T3 cell lines which are the standard fibroblast cell
lines, derived from Swiss albino mouse embryo tissue. 3T3 cell viability was observed at low concentrations
of the tested triterpenoids while they displayed anti-proliferative effect at higher concentrations.
Conclusion: Oleanolic acid 28-methyl ester (2) showed fairly different behavior from all the other
compounds tested and found to be the least cytotoxic compound. However, at 200 µM concentration,
it exhibited the same cytotoxicity with compounds 3, 9 and 10 around 58-59%. Among the
tested 13 compounds, 7 exhibited the most drastic decline for the viability from 12,5 µM to 25 µM
concentration. Compound 6 displayed the most cytotoxic effect, almost in all concentrations, particularly
at 6.25 and 25 µM concentrations while the highest cytotoxic effect at 50 µM was observed
for compound 11 among all the tested triterpenoids. As a result, all the tested OA derivatives
showed proliferative effect at 1,56 µM although no proliferative effect was observed for OA.
Moreover, OA exhibited higher cytotoxic effect than its derivatives, particularly at higher concentrations
(50, 100, 200 µM) with an exception for compound 11. Because, the latter showed highest
proliferative effect at lowest concentration, and highest anti-proliferative effect at highest concentration
which surpassed all the OA derivatives.
