Anti-tumor agents 255: Novel glycyrrhetinic acid–dehydrozingerone conjugates as cytotoxic agents

doi:10.1016/j.bmc.2007.06.027

Bioorganic & Medicinal Chemistry

Volume 15, Issue 18, 15 September 2007, Pages 6193-6199

https://doi.org/10.1016/j.bmc.2007.06.027 Get rights and content

Abstract

Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA–DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anti-cancer assay using nine different human tumor cell lines, most of the GA–DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED₅₀ values of 0.6, 0.8, and 0.9 μM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA–DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA–DZ conjugates are new chemical entities and represent interesting hits for anti-cancer drug discovery and development.

Graphical abstract

Introduction

Triterpenoids, including glycyrrhetinic acid (GA) (1), oleanoic acid (OA) (2), and ursolic acid (UA) (3), are widely distributed in the plant kingdom worldwide and show various pharmacological activities. Structurally, OA and UA have a carboxylic acid on the C17 position rather than the C20 position as in GA and also do not have a ketone at C11 as does GA. GA (1) is the main constituent in the roots of the medicinal plant licorice (Glycyrrhiza glabra L), which is broadly used as a flavoring and sweetening agent in food products. The wide-ranging biological activities of GA include anti-inflammatory,¹ anti-viral,² anti-allergic,3, 4 and anti-tumor promoting effects.⁵ OA (2) and its regioisomer UA (3) also have interesting biological activities.⁶ In addition, a well-known phenolic natural product, dehydrozingerone (DZ) (4), possesses anti-inflammatory, anti-oxidant, and anti-tumor promoting activities.⁷

Conjugation of two bioactive compounds is now accepted as an effective strategy for designing ligands, inhibitors, and other drugs.⁸ Our group has implemented the conjugation approach in drug discovery, which has led to promising results with varying compound classes.⁹ Therefore, based on the diverse bioactivities of the above-mentioned terpenoids as well as DZ, we initiated a structure activity relationship (SAR) study of terpenoid–DZ conjugation. Herein, we report the syntheses of terpenoid–DZ analogs and their unique cytotoxic activities (Fig. 1).

Section snippets

Results and discussion

Conjugation of DZ with the terpene acids GA, OA, and UA was achieved by a well-known esterification procedure using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as condensation reagent in the presence of 4-dimethylaminopyridine (DMAP). Among the three initial conjugates, GA–DZ (5), OA–DZ (6), and UA–DZ (7), only compound 5 displayed significant cytotoxic activity as described later. This exciting finding prompted us to synthesize novel GA–DZ analogs 29–38 as shown in

Conclusions

In summary, we found that conjugates between GA and DZ analogs showed significant cytotoxic activity, although the individual components, GA and DZ, and similar conjugates between DZ and similar terpenoids, OA and UA, did not. Novel GA–DZ analogs 5, 29, and 30, in which the methoxy and GA ester groups have an ortho relationship, showed significant cytotoxic activity against most of the tested cell lines. More interestingly, different DZ substitution patterns generated various cancer cell

General

The proton nuclear magnetic resonance (¹H NMR) spectra were measured on a Varian Gemini 2000 (300 MHz) NMR spectrometer with TMS as the internal standard. All chemical shifts are reported in ppm. Mass spectra were obtained on a Hitachi M-4100H mass spectrometer. Analytical thin layer chromatography (TLC) was performed on Merck pre-coated aluminum silica gel sheets (Kieselgel 60 F 254). Column chromatography was performed on a CombiFlash Companion system using RediSep normal phase silica columns

Acknowledgment

This investigation was supported in part by a grant from the National Cancer Institute (CA 17625) awarded to K. H. Lee.

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