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. 2024 Jun 3;15(6):879–884. doi: 10.1021/acsmedchemlett.4c00078

Synthesis Studies and the Evaluation of C6 Raloxifene Derivatives

David R Williams †,*, Levin Taylor IV †, Gabriel A Miter †, Johnathan L Sheiman †, Joseph M Wallace ‡,*, Matthew R Allen §, Rachel Kohler ‡, Claudia Medeiros ‡
PMCID: PMC11181480  PMID: 38894928

Abstract

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Methodology is described for the synthesis of C6 derivatives of raloxifene, a prescribed drug for the treatment and prevention of osteoporosis. Studies have explored the incorporation of electron-withdrawing substituents at C6 of the benzothiophene core. Efficient processes are also examined to introduce hydrogen bond donor and acceptor functionality. Raloxifene derivatives are evaluated with in vitro testing to determine estrogen receptor (ER) binding affinity and gene expression in MC3T3 cells.

Keywords: raloxifene derivatives, synthesis, methodology, estrogen binding affinity, bone properties

Raloxifene (1) is a selective estrogen receptor modulator (SERM) first developed by the Lilly Research Laboratories.1−3 As the FDA-approved drug, Evista, raloxifene is used to reduce osteoporotic fractures by decreasing bone resorption and increasing bone mineral density (BMD).4,5 However, the efficacy of 1 is far greater than what is predicted based solely on its effect on BMD.6−8 Since raloxifene has high affinity for binding to the estrogen receptor (ER), it exhibits prominent side effects associated with hormone therapy.9,10 As a result, safeguard limitations have been placed on the use of this prescribed medicine. In fact, several laboratories have presented crystallographic studies of human estrogen receptor with bound SERM derivatives11−13 to identify favorable interactions for treatment of breast cancer. Recent studies have indicated that raloxifene may induce a cell-independent mechanism that leads to improved collagen quality. Collagen plays a key role in establishing the material and mechanical properties of bone that are essential to fracture resistance.14,15 Studies have shown that the 6-hydroxy and, to a lesser extent, the 4’-hydroxy substituents of 1 are important for ER binding. These groups appear to mimic the 3- and 17β-hydroxy substituents of 17β-estradiol (17βe) (2) (Figure 1). Thus, our studies have examined alterations in C6 functionality in an effort to minimize hormonal side effects while maintaining positive outcomes for bone strength.16

Figure 1.

Figure 1

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Raloxifene (1) and 17β-estradiol (2).

Approximately one hundred derivatives of raloxifene have been prepared by studies in a number of laboratories in search of improved efficacy.17−20 In addition, recent studies have investigated dual use properties of raloxifene analogs in a variety of diseases.21,22 Over 90% of these variants contained C6–OH, C6–OCH3, or C6–H substitution. A large portion of this library has focused on modifications within the 2-aryl substituent attached to the core benzothiophene.23 This Letter explores the preparation and reactivity of raloxifene derivatives that incorporate C6 substitution unavailable using the established synthetic procedures. One important goal of our studies was to replace the C6–OH of raloxifene (1) with functionality that would participate in binding as hydrogen bond acceptor or donor sites, albeit with reduced affinity for the estrogen receptor. These preliminary results outline promising synthesis methods worthy of incorporation in an expanded investigation. Selected raloxifene derivatives have been examined with an in vitro ER binding assay for competitive displacement of 17βe (2) and with C3 gene expression in MC3T3 cells.

Initial efforts have explored the incorporation of electron-withdrawing groups and nitrogen-containing functionality at C6 of the benzothiophene core (Table 1). Although intermediate thioamides 4 are generally prepared in good yields, the cyclization to the benzothiophene core is adversely affected by the electronic withdrawing properties of C6 substituents. Thus, the desired cyclization fails completely using the standard conditions of catalytic methanesulfonic acid in CH2Cl2 at 0 °C.24−26 In fact, in these experiments, no reaction is observed at reflux, indicating decreased stability in the formation of the benzylic carbocation as a prerequisite for cyclization. Several attempts to improve the leaving group capability in 4 were unsuccessful.27 To this end, we have identified vigorous conditions using Eaton’s reagent (methanesulfonic acid with P2O5 (10% by weight)), which has afforded modest yields of purified benzothiophenes 5 (72%), 6 (63%), 7 (24%), and 9 (53%). Reduced yields of 8 were attributed to electronic factors induced by protonation of C6-pyridyl product 4d. While complete failure was observed in the attempted cyclization of 4f, an alternative method pioneered by Yang et al.28 was employed to obtain the trifluoromethyl derivative 11 from the nitrile 10, as well as the problematic C6 fluoro analog 7 (of Table 1; Figure 2). While the latter procedure afforded access to these electron-deficient derivatives, the expense of the starting nitriles (10) is prohibitive for large-scale synthesis of these particular analogs.

Table 1. Preparation of Thioacetamides and the Benzothiophene Core.

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a

Conditions: 1.1 equiv LDA, 1 equiv aldehyde (3), 1 equiv thioformamide, −78 °C to r.t., 4 h.

b

Conditions: 0.5 M in Eaton’s Reagent, 30 min.

Figure 2.

Figure 2

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Palladium induced formation of the benzothiophene core.

The C6-bromide 6 (Table 1) is a high-value product for further elaboration, as the presence of the bromide facilitates a variety of cross coupling processes. For example, Sonogashira cross couplings of 12 are generally successful and provide products as exemplified by 13 (76%) (Figure 3). Furthermore, Buchwald—Hartwig cross couplings with cyclic secondary amines afford new C6 derivatives such as the C6 morpholino 14 in multigram scale reactions. Raloxifene triflates have been reported via low-yielding reactions of 1, and these triflates also undergo Stille cross-coupling reactions in moderate yields.29 An issue for polar amines, such as 14, is the coelution of a persistent impurity which may hamper the isolation of highly purified quantities (>99% pure) necessary for biological evaluations. In addition to these standard techniques, 6-bromo-benzothiophene 6 (from Table 1) readily undergoes halogen-metal exchange to provide the corresponding lithium reagent for introduction of a host of electrophiles. Table 2 illustrates four standard reactions with aldehydes, ketones, and acyl chlorides, as demonstrated by the formation of 15, 16, 17, and 18.

Figure 3.

Figure 3

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Examples of cross-coupling reactions of C6-bromide 12.

Table 2. Synthesis of 6-Substituted Benzothiophenes via Halogen-Metal Exchangea.

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a

Conditions: 1 equiv thiophene, 2.2 equiv tBuLi, 0.1 M in THF, −78 °C, then add electrophile (excess) at −78 °C.

In the cases of C6 acylation (entries 3 and 4), the reactive lithio species from 6 leads to small amounts of ketone 19 as a byproduct (10%) that is readily separated by flash chromatography. The hydride reduction (LiAlH4, THF at 0 °C) of ethyl ester 17 leads to corresponding primary benzylic alcohol 20 (82%) of Scheme 1. The benzylic alcohols of 15 and 20 are protected as the corresponding tert-butyldimethylsilyl (TBS) ether 21 and 22 in excellent yield (TBSCl, imidazole, CH2Cl2, r.t., 90% yield). Similarly, we prepared the corresponding methoxymethyl (MOM) ether 23 under standard conditions.

Scheme 1. Alternative Acylation Procedure via C3 Bromination.

Scheme 1

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The search for a mild acylation method has led to an alternative process that offers opportunities for broad applications via low temperature lithiation at C3. A general and high-yielding process for C3 bromination of the benzothiophene core is exemplified by the examples of 21, 22, and 23 (Scheme 1). The purified bromides 24a,b,c are subsequently used for halogen-metal exchange at −78 °C to give a reactive lithio species which provides the ketones 25a,b,c upon reaction with the Weinreb amide 26. Furthermore, alcohol 25d was also readily available via the treatment of 25a with TBAF for deprotection of the silyl ether (95% yield). The preparation and introduction of 26 offer an important advantage since it is readily purified by flash chromatography and avoids use of the acid chloride salt which has been used in previously published acylation procedures. In these cases, the acid chloride salt consumes one equivalent of lithium reagent. Based on 2:1 stoichiometry of the aryl lithium and the acylation reagent, we observed complete consumption of the starting bromides 24a,b,c and often recovered 15%–20% of 26. Yields of ketones 25a,b,c generally ranged from 44% to 60% with isolation of as much as 30% of the reduced benzothiophene. Prolonged reaction times and high temperatures failed to provide improved yields of product. When these reactions were quenched with D2O, no evidence of deuterium incorporation was found. In fact, we have measured approximately 70% deuterium incorporation after directly quenching the halogen-metal exchange with D2O. The choice of solvent is significant, as THF led to increased amounts of reduced benzothiophene, whereas pentane in ether (60:40 by volume) led to the best results for deuterium incorporation. While the aryl lithium may have limited stability in anhydrous THF, the amide 26 was insoluble in pentane/ether, and further attempts to improve the stability of the C3 lithio species by addition of TMEDA, DMPU, or HMPA in THF solutions also led to reduced yields. These experiments have demonstrated great potential for the use of two sequential lithiations at C6 and C3 of the core benzohiophene to construct a wide variety of raloxifene derivatives, and therefore, we continue to examine alternative solvents to gain better overall yields.

Our studies have also examined the Friedel–Crafts acylation of novel C6-substituted benzothiophenes from Tables 1 and 2 en route to raloxifene analogs.30,31 We have prepared the acid chloride salt 27 of Table 3 by treatment of the known carboxylic acid32 with oxalyl chloride in CH2Cl2 solution containing small amounts of DMF. The resulting hydrochloride salt 27 is filtered and triturated with small amounts of solvent. As a white powder, it is easily stored at room temperature under argon to maintain an anhydrous condition. Unfortunately, electron-withdrawing groups at C6 of the benzothiophene dramatically reduce the reactivity of the enamine moiety. While the solid 27 is readily measured and introduced into these reactions, it shows low solubility in most organic solvents. As shown by the examples of Table 3, acylations using chloride 27 require prolonged reaction times and higher temperatures (140 °C) as compared to the usual published procedures. In the presence of catalytic 4-dimethylaminopyridine (DMAP), the desired ketones 28 through 34 (Table 3) are obtained in 53% to 72% yields. As expected, derivatives 21, 22, and 23 from Scheme 1 were not amenable to these robust acylation conditions.

Table 3. Friedel–Crafts Acylation of Benzothiophenes at 140 °Ca.

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a

Conditions: 1 equiv thiophene 5, 1.1 equiv HCl salt 40, cat. DMAP, 1 M in chlorobenzene, 140 °C for 9–12 h.

Our preliminary studies have demonstrated the synthesis of novel raloxifene derivatives via the installation of the 2-aryl component upon 1,4-conjugate addition of 4-(tert-butyldimethylsiloxy)phenyl magnesium bromide reagent with our enamide acylation products. Five representative examples illustrate the formation of novel raloxifenes 35 through 39. These derivatives have not been readily accessible via standard protocols. Flash silica gel chromatography of the crude reaction mixture following the Grignard addition directly led to TBS silyl ether cleavage using tert-n-butylammonium fluoride (TBAF). The final products are obtained by flash chromatography to derive C6-subtituted raloxifenes in >96% purity for biological evaluations.

To verify that our analogs had reduced ER binding affinity, fluorescence polarization (FP) tests were performed, where selected derivatives 13, 35, 36, 37, and 39, were compared to 17βe (2) using an ER-alpha-competitor assay kit (PolarScreen ER Alpha Competitor Assay Green, Thermo Fisher). FP of fluorochrome tracers bound to ER was measured (EnVision 2102 Multilabel Plate Reader, PerkinElmer) in 8 triplicate serial dilutions of compound concentrations ranging from 10–10 to 10–6 M. The output degree of light polarization for each well was plotted versus compound concentration and fit to a nonlinear curve in GraphPad PRISM (9.5.1) to produce an IC50 value for each compound (half of the maximal concentration required to reduce tracer displacement due to binding). Results indicated that analogs 35 and 39 had significantly lower ER binding affinity compared to 17βe (2), as shown by the high compound concentration needed to detect a change in tracer binding (Figure 4; Table 4). We also sought confirmation of these results by assessing in vivo effects, C3 gene expression was analyzed in MC3T3-E1 Subclone 4 (ATCC CRL-2593; Manassas, VA) murine preosteoblasts fed media dosed with analogue treatments or DMSO at concentrations of 1, 10, and 100 nM for each treatment, with 2 replicates. RNA extractions were performed after 2 days of growth using Bioline kit without Trizol (High Capacity RNA to cDNA synthesis kit 4387406). Gene expression was performed, with all samples assessed in triplicates (Life Technologies Taqman Fast Advanced Buffer and Assay Mm00437838, assessed in a QuantSTudio 3 Real-Time PCR), and qPCR data was analyzed using the Livak method. C3 expression was not significantly upregulated in most analogs compared to controls (Figure 4), further indicating that ER binding affinity was successfully reduced.

Figure 4.

Figure 4

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Analog characterization and in vitro testing. Solutions (nM) of derivatives were prepared in the buffered medium supplied in the commercial test kits. (A) IC50 values from repeated fluorescence polarization tests indicate estrogen-binding affinity. P-values from one-way ANOVA-post hocs shown with * for p < 0.05. (B) C3 gene expression in MC3T3 cells treated with various analog concentrations, normalized by GAPDH. P-values from one-way ANOVA post hocs shown with * indicating p < 0.0001.

Table 4. Grignard Reactions for the Formation of Raloxifene Derivatives.

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Entry Enamide (R) C6-Raloxifene Derivative (% yield)
1 28 R = OCF3 35 R = OCF3 (75)
2 29 R = Br 36 R = Br (73)
3 30 R = F 37 R = F (73)
4 25d R = CH(CH3)OH 38 R = CH(CH3)OH (44)
5 34 R = C(O)NMe2 39 R = C(O)NMe2 (70)
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The goal of our studies is to identify raloxifene analogs with little or no estrogen receptor (ER) signaling while modulating bone quality and mechanical properties. Preliminary efforts selected compound 39 for these investigations. The G610C mouse model of osteogenesis imperfecta (OI) was used in these in vivo studies, and mice were bred in-house with wild-type (WT) females to produce G610C and WT offspring. A description of the data and methodology from the in vivo studies is too extensive to include in this letter, but it appears in a separate publication.33 The proof of concept shows that 39 has low ER affinity and positive impacts on the ability of the OI bone to resist fracture at the expense of reduced preyield mechanical behavior. In fact, treatment with 39 did not improve preyield mechanical properties, but postyield and total displacement were significantly increased. Analog 39, together with loading, increased 4-pt bending displacement, strain, and toughness of G610C bone. The strongest effects were apparent in loaded bone, where treatment with 39 is combined with a bone anabolic stimulus. Our findings suggest that toughness of de novo bone tissue may be positively impacted by treatment with 39. This communication details procedures that offer a robust protocol for the evaluation of a wide variety of derivatives made available by our investigation.

In conclusion, this study examined new opportunities for the preparation of raloxifene derivatives. Specifically, the scope of C6 substitution has been limited in prior work. In this preliminary study, synthesis methods and techniques have been devised to expand the scope of the available compounds. Substitution at C6 has addressed the preparation of benzothiophenes which provide reduced binding affinity for the ER receptor. Results also outline pathways for the introduction of various hydrogen bond donor and acceptor functionalities at C6 of the raloxifene core. Further studies to assess the biology of C6 raloxifene derivatives are currently in progress.

Glossary

Abbreviations

ER

estrogen receptor

SERM

selective estrogen receptor modulator

BMD

bone mineral density

17βe

17β-estradiol

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00078.

  • Experimental procedures; full characterization data for all final products; characterizations of intermediates in the synthesis sequence listed as compounds 4a, 5, 4b, 6, 4c, 7, 4d, 8, 4e, 9, 4f, 11, 13, 14, 15–18, 20–26, and 28–39; HPLC proof of purity for products 13, 35, 36, 37, 38, and 39 (PDF)

Author Present Address

∥ Momentive Performance Materials, Sistersville Site, 10851 Energy Highway, Friendly, WV 26146

Author Present Address

⊥ U.S. Army, Building 10230 North Riva Ridge Loop, Fort Drum, NY 13602, USA

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This project was partially supported by the Indiana Clinical and Translational Sciences Institute funded by Grant Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. (DRW, JMW, MRA) Partial support was provided by Indiana University (Vice Provost for Research through the Research Equipment Fund). (DRW) This material is based upon work supported in part by the National Science Foundation under Grant CHE2102587. (DRW). Partial support was provided by the National Institutes of Health (NIH R01: AR072609). (JMW)

The authors declare no competing financial interest.

Supplementary Material

ml4c00078_si_001.pdf (1.9MB, pdf)

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