Abstract
In order to develop new oleanolic acid (OA) derivatives endowed with improved antitumor activities, for the first time, a number of new hybrid compounds were reported by combining OA or 3-oxooleanolic acid with appropriate H2S-donor moiety, coupled via a suitable linker. The anti-tumor evaluation indicated that they exhibited excellent anti-cancer activities against the tested cancer cell lines. Moreover, 18d with 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione moiety as H2S donor and β-alanine as the linker, showed more potent cytotoxicity against the tested cancer cell lines than OA and 3-oxooleanolic acid, especially for A549 cells. Furthermore, the preferred compound, 18d, preferentially accumulates in cancer cells (13.6 μM) over the matched normal cells LO2 (>100 μM) in vitro. The improved antitumor activity of this hybrid was probably due to its H2S-releasing capability.
Highlights
One of the major causes of death in patients is cancer, and a major factor to explore in cancer treatment is novel chemotherapy
The synthesis of oleanolic acid–hydrogen sulfide donor hybrids and 3-oxooleanolic acid–hydrogen sulfide donor hybrids are outlined in Schemes 1 and 2, respectively
oleanolic acid (OA) or 3-oxo-OA was directly modified with different hydrogen sulfide (H2 S) donors in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
Summary
One of the major causes of death in patients is cancer, and a major factor to explore in cancer treatment is novel chemotherapy. The design of novel antitumor therapeutic agents, including oleanolic acid (OA) activities, represents an area in need of urgent attention. The optimization of compounds derived from natural origins represents one of the promising strategies which is widely used in seeking and developing anticancer drug molecules [1]. On the basis of the structure of OA, there have been multiple studies concerning the structural modification and improvement of their antitumor activities and aqueous solubility [6,7]. Many hybrid OA compounds have been synthesized, including amino acid/dipeptide prodrugs of OA [4,8,9] and nitric oxide (NO) donor hybrid OA compounds [4,10,11,12,13], which showed significantly improved antitumor activity and pharmacokinetic properties. To the best of our knowledge, there were no reports focused on hydrogen sulfide (H2 S) donor hybrid OA compounds
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