Abstract
Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti-inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH-glycyrrhetinic acid, the novel synthetic derivative methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug-resistance phenotype. It causes cell death by inducing the intrinsic caspase-dependent apoptotic pathway.
Highlights
Organic molecules synthesized by plants constitute a rich reservoir of biologically active compounds
The number of apoptotic cells increased with the time of incubation, and with increasing compound concentration. 89.2 % of KB-3-1 cells were detected as apoptotic following 24 h of incubation in the presence of 1 mm 12, so 12 induces dose- and time-depended apoptotic cell death. These data indicate that the decrease in viability of cancer cells exposed to the novel glycyrrhetinic acid derivatives occurred by apoptosis, and that 12 had the greatest potency
In this report we describe the synthesis of the new glycyrrhetinic acid derivative methyl 2-cyano-3,12-dioxo-18bH-olean
Summary
Organic molecules synthesized by plants constitute a rich reservoir of biologically active compounds. An abundantly occurring triterpene, has been converted into 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and other structurally related analogues (CDDO-Me, CDDO-Im, CDDO-CN; Scheme 1 A).[7,8,9] All of these synthetic derivatives were reported to display various bioactivities: cytoprotection, cancer cell growth inhibition, apoptosis induction, and inhibition of the production of NO induced by INF-g in mouse macrophages.[7,8,9,10,11,12] CDDO and CDDO-Me are currently in clinical trials for cancer treatment, and have been shown to effectively suppress the growth of a broad spectrum of solid and hematologic cancer cell types, both in vitro and in mouse models bearing xenografted human tumors.[9,10,11,12] During the development of CDDO, it was found that the 2-cyano-1-en-3-one in ring A, and the 9(11)-en-12-one in ring C are essential for the biological activity of CDDO and its analogues.[13,14,15].
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