Synthesis and Biological Evaluation of Second-Generation Tropanol

Feb 3, 2015 - Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Sölvegatan 19, BMC DIO, S-22184 Lund, Swe...
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Synthesis and Biological Evaluation of Second-Generation TropanolBased Androgen Receptor Modulators Henrik Sundén,†,○ Mareike C. Holland,† Pekka K. Poutiainen,§,∥ Tiina Jaä s̈ kelaï nen,⊥,# Juha T. Pulkkinen,§ Jorma J. Palvimo,#,∇ and Roger Olsson*,†,‡ †

Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-41296 Gothenburg, Sweden Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Sölvegatan 19, BMC DIO, S-22184 Lund, Sweden § School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland ∥ Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States ⊥ Institute of Dentistry, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland # Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland ∇ Department of Pathology, Kuopio University Hospital, FI-70029 Kuopio, Finland ‡

S Supporting Information *

ABSTRACT: To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.



design larger antiandrogens.21−23 However, in general, larger molecules often face problems associated with physiological distribution and permeability.24 Other strategies to treat CRPC rely on antagonists with a strong binding affinity such as the highly potent antiandrogen enzalutamide, formerly known as MDV3100, discovered by the Sawyers/Jung groups, that has become available for patients with metastatic castrationresistant prostate cancer. Enzalutamide has approximately 5fold higher binding affinity for the AR compared to the bicalutamide.25−27 As a part of our ongoing research on nuclear hormone modulators28−35 we reported, in 2008, the pharmacological characterization of AR modulators based on the tropanol scaffold31,36 which later led to the identification of ACP-105 (Figure 1), an oral and selective AR modulator.37,38 In addition to a thorough study of metabolic clearance, the SAR revealed that small changes in the aryl substitution pattern lead to drastic effects on potency. For example, the removal of the methyl group in the 3-position of the phenyl, converted the AR agonist into an AR antagonist (Figure 2). Furthermore, the compound also displayed antagonistic activity for the mutant T877A. In contrast to previous efforts in the area of mutation resistant AR antagonists, these AR antagonists were slightly smaller as

INTRODUCTION Prostate cancer is the most common form of cancer found in men in developed countries, and its therapy remains a challenge. Because prostate cancer development and growth is initially dependent on androgens, inhibition of the androgen receptor (AR) signaling is of great medicinal interest for cancer treatment. Several nonsteriodal antiandrogens have been developed for this purpose,1−8 and a few of these, such as flutamide (Flu), bicalutamide (Bic), and nilutamide (Figure 1),9−12 have been clinically available for a long time. However, prostate cancer patients often develop resistance to antiandrogen treatment with these drugs.13−16 In the hormone refractory form of the disease, i.e., castration resistant prostate cancer (CRPC), stopping of unsuccessful hormonal therapy can often lead to a transient improvement in the condition, a phenomenon referred to as antiandrogen withdrawal syndrome or response.17 A plausible explanation for the phenomenon is a mutation in the ligand-binding domain (LBD) of the AR that develops during the treatment with Bic or Flu, converting these antagonists to agonists. The general trend seen in the most common AR mutations is a replacement of a large amino acid with a smaller one, e.g., T877 with A and W741 with L or C, thus creating a more spacious LBD. As a consequence, Bic behaves as an agonist with mutants W741L and W741C and Flu with T877A.18−20 To circumvent agonistic effects in the mutated ARs, a common approach in medicinal chemistry is to © 2015 American Chemical Society

Received: November 11, 2014 Published: February 3, 2015 1569

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Figure 3. DFT (B3LYP-D3) optimized structures of 1 and 2. The energy differences between the nitrogen conformers are 9 and 11 kJ/ mol for 1 and 2, respectively.

Having found a possible explanation for the observation that the smaller, nonmethylated tropane 2 exerts antagonism and not agonism, we decided to make a library of compounds omitting the methyl in the 3-position to probe if the antagonistic trend persisted and could be improved. The syntheses of the arylated nortropines 2 and 7 commenced with quantitative Boc-deprotection of nortropine 3 with TFA in CH2Cl2 (Scheme 1). Arylation of the TFA-salt 4

Figure 1. Androgen modulators.

Figure 2. Subtle differences in the molecular structure impact the biological response.

Scheme 1. Syntheses of 2 and 7

compared to the agonists. It was speculated that this could be a consequence of a conformational change between the tropanol and phenyl due to the lack of a methyl group in the aromatic ring. Herein, we report the synthesis and biological evaluation of novel structures based on the molecular topology found in tropanol 2. These new aryltropanols are in some cases equipotent to Bic but, in contrast to Bic, do not show agonist activity for the mutant W741L.



RESULTS AND DISCUSSION The lowest energy conformations of 1 and 2 were investigated to study the methyl dependence of the agonist and antagonist activities of 1 and 2, respectively. A conformational search for compounds 1 and 2 revealed that the presence of the 3-methyl leads to a nitrogen inversion of the tert-amine, resulting in a distinct topology difference for 1 as to compared to 2 (Figure 3). For 1, the aromatic 3-methyl experiences a more unfavorable steric interaction with the tropanol scaffold and the aromatic ring is forced out of the favorable N-Ar orbital overlap. Consequently, the 3-methyl of the aromatic ring is rotated away from the ethylene bridge, causing an inversion of the amine (Figure 3a), which is 9 kJ/mol lower in energy than the alternative nitrogen conformer (Figure 3b). The lowest energy conformation of compound 2 positions the aromatic ring away from the ethylene bridge in plane with the lone pair of the nitrogen (Figure 3c). This conformation is 11 kJ/mol lower in energy than then the inverted conformer (Figure 3d). Consequently, conformer c of 2 will be favored by a Boltzman distribution of 65:1 (310 K).

was performed with the fluorine-substituted aryls 5 and 6 in the presence of K2CO3 at 120 °C in DMSO to give the arylated amines 2 and 7, respectively, in high yields. The synthesis of the 3-exo-methyl tropanol 11 was performed in a two-step sequence starting with the hydrogenolysis of benzyl amine 9 with Pd/C (5 mol %, 10 wt %) under H2 atmosphere in EtOH (Scheme 2). Subsequent nucleophilic aromatic substitution with 4-fluoro-2-trifluoromethylbenzonitrile 6 gave 11 in quantitative overall yield. To introduce sulfone amines to the nortropine scaffold, 7 was oxidized to the corresponding ketone. Initial oxidation attempts under Swern conditions did not provide satisfactory results, but to our delight oxidation with Dess−Martin periodane (DMP) in dry CH2Cl2 gave 12 in 92% yield. Subsequently, ketone 12 was converted to benzyl amine 13 in a reductive amination process using NaBH(OAc)3 and AcOH to give 13 in 66% yield after recrystallization from MeOH (Scheme 3). Introduction of the sulfonyl group proved to be difficult, and initial attempts to react benzyl amine 13 with sulfonyl chloride remained unsuccessful. Therefore, the benzyl-protection group was removed prior to sulfonylation. 1570

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at elevated temperatures. However, a drastic improvement could be accomplished with an H-Cube supported reduction. Low temperature proved to be a key parameter to circumvent the formation of byproducts, and optimal conditions were found using Pd(OH)2/C as the catalyst in the H-Cube at 20 bar H2 and 15 °C to give 14 in 70% crude yield. Compound 14 was used without purification in the next step. Sulfonamines 15 and 16 were synthesized using triethyl amine and sulfonyl chloride and could be isolated in 39% and 45% yield, respectively, over two steps (Scheme 3).

Scheme 2. Synthesis of 3-exo-Methyl Tropanol 11



BIOLOGICAL EVALUATION Structure−activity relationship (SAR) studies (Table 1) were carried out by using luciferase reporter gene assays and [3H]R1881 competitive receptor-binding assays. The biological activities of the compounds were compared with those of testosterone (T) and Bic. The measured activity differences were considered statistically significant when p < 0.05. The reporter assays measured the transcriptional activity of the AR. To that end, we used a firefly luciferase (Fluc) gene construct driven by an AR regulated rat probasin promoter fragment which was cotransfected with AR expression constructs (wild-type AR in wtAR antagonism assays and LBD-mutated ARs in mutated AR agonism assays) into COS-1 cells. When the cells were exposed to the AR agonist testosterone, the wtAR was activated, resulting in increased transcription of the reporter gene and thereby augmented synthesis and activity of luciferase. Addition of antiandrogens in combination with the agonist inhibited the wtAR activity, leading to a decreased luciferase activity, which is directly proportional to the inhibitory activity of the antiandrogen (Figure 4).39 The results obtained from these assays with wild-type AR are listed in Table 1. Bicalutamide reduced the total luciferase activity by 85% when 10 μM antiandrogen and 50 nM testosterone concentrations were used. The in vitro activity screening revealed that 2 and 7 expressed antagonistic behavior equal to or stronger than that of bicalutamide (Table 1, entries 3 and 4). Compound 2 reduced the total luciferase activity by approximately 90%, and 7 showed an 87% reduction of the activity. Tropinol 11 yielded a 72% inhibition of Luc activity

Scheme 3. Syntheses of 12, 13, 15, and 16

Hydrogenolysis with Pd/C under an atmosphere of H2 proved to be insufficient, with long reaction times and nitrile reduction Table 1. Biological Evaluation of the Aryl-tropanol Compoundsa no.

RBI IC50 (nM)

T Bic 2 7 11 12 13 15 16 ACP-105

4.27 86.9 31.7 39.8 29.3 66.0 233 2650 2040 2.11

IC50 4.17 8.69 3.17 3.98 2.93 6.60 2.33 2.65 2.04 2.11

× × × × × × × × × ×

10−09 10−08 10−08 10−08 10−08 10−08 10−07 10−06 10−06 10−09

Ant % wtAR ± ± ± ± ± ± ± ± ± ±

0.05 0.06 0.05 0.07 0.06 0.06 0.07 0.09 0.11 0.05

100 15.5 10.5 13.0 27.8 20.7 47.9 84.2 90.4 104.8

± ± ± ± ± ± ± ± ± ±

14.5 2.0 1.7 0.9 3.8 1.2 2.0 5.0 3.2 3.8

Ago % T877A 100 3.4 47.0 45.5 69.3 48.5 4.3 25.5 3.4 114.8

± ± ± ± ± ± ± ± ± ±

5.7 0.2 0.7 5.3 7.2 3.1 0.5 1.4 0.5 2.1

Ago % W741L 2 100 0.7 0.7 4.5 1.1 1.4 0.6 0.6 70.9

± ± ± ± ± ± ± ± ± ±

0.3 4.7 0.1 0.1 0.2 0.1 0.1 0.1 0.1 11.2

a

Relative binding inhibition (RBI) was measured using a whole COS-1 cell assay in which the cells were transfected with pSG5-hAR (human AR expression construct), exposed to synthetic AR agonist [3H]R1881 in the absence (with vehicle, ethanol) and the presence of a wide range of compound concentrations. wtAR antagonism activity was determined by firefly luciferase (Fluc) reporter construct driven by an AR-regulated rat probasin promoter fragment cotransfected with pSG5-hAR into COS-1 cells. The relative transcriptional activity of AR in the presence of 50 nM testosterone (set as 100) together with sample concentrations 1 μM. Results are presented as mean ± SD of three independent experiments. Mutated AR agonism was determined by the Fluc gene construct cotransfected with AR expression constructs encoding T877A or W741L mutants into COS-1 cells. The relative transcriptional activity of AR in the presence of tested compound alone (1 μM). Results are presented as mean ± SD of three independent experiments 1571

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Figure 4. Wild-type AR (wtAR) antagonism assay. The relative transcriptional activity of AR in the presence of 50 nM testosterone (set as 100) together with tested compound in increasing concentrations (0.1, 1.0, and 10 μM). Results are presented as mean ± SD of three independent experiments.

(Table 1, entry 5), showing that the introduction of a methyl group to enhance metabolic stability also gives less transcriptional inhibition as compared to 2 and 7.37 Ketone 12 proved to be less potent than 2 and 7 and indicates that a hydroxyl moiety exhibits enhanced inhibition as compared to a ketofunctionality. This could be rationalized by potential H-bonding of the hydroxyl group to asparagine 705 (Asp705) and threonine 877 (Thr877) which would improve binding interactions. Amine containing ligand 13 inhibits transcription to a level of 50%, and sulfonamides 15 and 16 hardly inhibit transcription at all, indicating that spacious groups substituted on the amine are detrimental to the inhibition of AR wild-type. Moreover, our compounds were tested using AR LBD mutants T877A and W741L, which are commonly observed in prostate cancer patients.39−42 Compounds 2, 7, 11, and 12 were found to maintain their agonist behavior with mutant T877A and show almost no agonism with W741L in contrast to Bic with total loss of its inhibitory ability in W741L (Figure 5). Amines 13 and 16 display low agonism with mutants T877A and W741L, and a trend of larger substituents giving low agonistic potencies can be seen (benzyl 13 and SO2Et 16 are better than SO2Me 15). A reasonable explanation is that the larger amines 13, 15, and 16 interact with α-helix 12, which consequently leads to diminished agonism for these compounds. To further characterize the compounds, biological activity log IC50 values were determined. Relative binding inhibition (RBI) was measured in COS-1 cells transfected with an AR expression vector and exposed to a synthetic AR agonist [3H]R1881 in the absence (with vehicle, ethanol) and presence of AR antagonist. Dose−response curve fittings (e.g., in Figure 6) were performed with GrafPad Prism56 using least-squares fit with logarithmic scale and variable slope. Results from the cell binding studies showed that our most efficient compounds 2 and 7 inhibit the radioligand binding to a greater extent than bicalutamide. The fitted curves of 2 and 7 indicate 2-fold higher inhibitory potencies than Bic. Tropinol 11 also inhibits radioligand binding and is equipotent to 2 and 7 with a RBI IC50 of 29.1 nM. Compound 12 also inhibits radioligand binding, although the absence of hydrogen bonding capabilities

Figure 5. Mutated AR agonism assay. The relative transcriptional activity of AR W741L (upper panel, with 1.0 μM Bic set as 100) and AR T877A (lower panel, with 50 nM testosterone set as 100) in the presence of tested compound alone (1.0 and 10 μM). Results are presented as mean ± SD of three independent experiments.

seems to cause a loss in potency in comparison to hydroxyl analogue 7 displaying the same potency as 12 and Bic. Amines 13, 15, and 16 gave only micromolar potencies, which correlate well to the competitive binding assay.



CONCLUSION In summary, we have characterized compounds with a tropanol-based scaffold as AR wild-type and AR mutant inhibitors. The scaffold has shown to be sensitive to changes on the aryl ring. Substitution of a methyl by a proton in the 3position has a drastic effect on the molecular topology, leading to compounds with agonistic and antagonistic activities, respectively. The most potent compounds 2 and 7 expressed antagonistic behavior equal to or stronger than that of Bic and have pKis in the high 7. Moreover, 2, 7, 12, 13, 15, and 16 show little or no agonism activity with AR mutant W741L that is activated by Bic and observed in prostate cancer patients treated with Bic. Interestingly, amines 13 and 16 execute a weak inhibition of AR wild-type, however, they show low to no agonistic effect on the AR LBD mutants. The focused set of small ligands investigated constitute an interesting starting 1572

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Figure 6. Relative binding inhibition (RBI) was measured using competitive whole cell binding assay in the presence of 1.34 nM the [3H]R1881 with a wide range of compound concentrations to obtain their binding inhibition curves.

point for the development of new antiandrogens that are active for both AR wild-type and the AR LBD mutants.



ASSOCIATED CONTENT

S Supporting Information *

Materials and methods, experimental data for compounds 2, 7, 10−16, purity measurements, computational models. This material is available free of charge via the Internet at http:// pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author

*Phone: +46 76 887 42 17. E-mail: [email protected]. Address: Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Sweden. Present Address ○

For H.S.: Chalmers University of Technology, Chemical Engineering, Kemivägen 10, 41296 Gothenburg, Sweden.

Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS We thank Anja Probst-Larsen (University of Copenhagen) and Per-Ola Norrby for fruitful discussions and computational technical support. Financial support from The Foundation for The North Savo Cancer Foundation (P.K.P.), The Alfred Kordelin Foundation (P.K.P.), The Finnish Cultural Foundation (North Savo Regional Fund) (P.K.P), the Finnish Cancer Organisations (J.J.P.), the strategic funding of the University of Eastern Finland (J.J.P.), and the Sigrid Jusélius Foundation (J.J.P.) are gratefully acknowledged.



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