Original articleSynthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation
Graphical abstract
Highlights
► 28 New Sulindac analogs as modulators of tRXRα-dependent AKT activation were synthesized. ► Binding assay was used to test the 28 compounds for SAR study. ► A new scaffold was found with improved biological properties.
Introduction
Retinoid X receptor-α (RXRα) is a unique member of the nuclear receptor (NR) superfamily, playing an important role in many biological processes ranging from apoptosis, cell differentiation and growth to lipid metabolism [1], [2], [3]. RXRα acts primarily as a ligand-dependent transcription factor through forming homodimer with itself or heterodimer with other members of the NR family. Structurally RXRα shares a modular organization with other nuclear receptors, consisting of three main functional domains: an N-terminal region where the ligand-independent transcriptional activation function (AF-1) is located, a DNA-binding domain and a ligand-binding domain (LBD) [2]. The transcriptional activity is directly mediated by the LBD and thus the LBD has been the most studied domain. The LBD possesses a ligand-binding pocket (LBP) for the binding of small molecule ligands, a transactivation function domain termed AF-2 composed of Helix 12 (H12) of the LBD, a coregulator binding surface, and a dimerization surface. Numerous ligands targeting the LBP have been designed and reported [4], [5]. Natural RXRα ligand 9-cis-retinoic acid (9-cis-RA) and synthetic RXR ligands (rexinoids) have been effective in preventing tumorigenesis in animals [6] and RXRα has been a drug target for therapeutic applications, especially in the treatment of cancer [7]. Targretin, a synthetic RXR-selective retinoid, was approved for treating cutaneous T-cell lymphoma [8], [9], and it has also been explored for the treatment of other forms of cancer such as lung cancer, breast cancer, and prostate cancer [10], [11], [12].
Sulindac, a nonsteroidal antiinflammatory drug (NSAID) drug, has been investigated as a cancer chemopreventive agent, because of its potent induction of apoptosis and inhibition of cancer cell growth [13], [14], [15], [16]. It has been documented that the anti-cancer effect of Sulindac can be mediated through COX-2-independent mechanisms [14], [15], [17]. We recently reported that Sulindac induces apoptosis in several cancer cell lines and primary tumors by binding to an N-terminally-truncated RXRα (tRXRα) [18]. Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K), activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α interaction, leading to activation of the death receptor-mediated apoptotic pathway [18]. Furthermore, we showed, a designed Sulindac analog K-80003 (2) (Fig. 1) exhibits increased affinity to RXRα without COX inhibitory activity, and displays enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals, demonstrating the feasibility of developing a new generation of RXRα-specific molecules for therapeutic application or mechanistic studies of RXRα. Here we present the synthesis, SAR studies and biological evaluation of a series of K-80003 derivatives and the discovery of a new scaffold 30.
Section snippets
Results and discussion
Compared to Sulindac (1, Fig. 1), compound 2 displays an increased binding to RXRα and potency in inhibiting tRXRα-dependent AKT activation [18]. Compounds 1 and 2 differ in the replacement of the sulfide group in 1 by an isopropyl group in 2 at R1 (Fig. 2). Thus, for the first round of SAR study we investigated the effects of various substituents of R1 (Fig. 2) on the binding affinity to the RXRα LBD. Scheme 1 outlines the synthetic chemistry used for the preparation of this group of compounds
Chemistry
The synthesis started from the Perkin reaction of 4-fluorobenzaldehyde 31 with propionate anhydride [24], in which K2CO3 was used as a base to substitute hygroscopic sodium propionate, providing the desired product 32 in 83% yield (Scheme 1). Catalytic hydrogenation in the presence of Pd/C and under 10 atm of hydrogen gave carboxylic acid 33 in 90% yield. Polyphosphoric acid (PPA)-promoted intermolecular Friedel–Crafts acylation reaction produced indenone 34 in 74% yield. Treatment of indenone
Conclusion
In conclusion, we have described the synthesis and SAR studies on a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRα-dependent AKT activation. Compound 30, a geometric isomer of the original lead 2 and with better binding activity and improved biological effects, could bind to the LBP of RXRα in a different mode from 2, which offers a new design strategy. Compound 30 is a promising lead for further optimization studies and may find application as a small molecule
General methods
Melting points (M.p.) were determined on a Yanaco MP-500 micro melting point apparatus and were uncorrected. Infrared spectra were measured with a Nicolet Avatar 360 FT-IR spectrometer using film KBr pellet techniques. 1H and 13C NMR spectra were recorded in CDCl3 or CD3OD on a Bruker 400 spectrometer with tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield from TMS. Mass spectra were recorded by a Bruker Dalton ESquire 3000 plus liquid
Acknowledgments
This work was supported by Grants from the U.S. Army Medical Research and Material Command (W81XWH-11-1-0677), the National Institutes of Health (CA140980, GM089927), the 985 Project from Xiamen University, the National Natural Science Foundation of China (NSFC-91129302 and 20832005).
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Equal contribution.