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. 2019 May 9;10(6):863–868. doi: 10.1021/acsmedchemlett.8b00440

Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling

Samuel Bouchet †, Camille Linot ‡, Dusan Ruzic §, Danica Agbaba §, Benoit Fouchaq ∥,⊥, Joëlle Roche ⊥,#, Katarina Nikolic §, Christophe Blanquart ‡,⊥, Philippe Bertrand †,⊥,*
PMCID: PMC6580376  PMID: 31223439

Abstract

graphic file with name ml-2018-00440z_0004.jpg

Dissymmetric cross metathesis of alkenes as a convergent and general synthetic strategy allowed for the preparation of a new small series of human histone deacetylases (HDAC) inhibitors. Alkenes bearing Boc-protected hydroxamic acid and benzamide and trityl-protected thiols were used to provide the zinc binding groups and were reacted with alkenes bearing aromatic cap groups. One compound was identified as a selective HDAC6 inhibitor lead. Additional biological evaluation in cancer cell lines demonstrated its ability to stimulate the expression of the epithelial marker E-cadherin and tumor suppressor genes like SEMA3F and p21, suggesting a potential use of this compound for lung cancer treatment. Molecular docking on all 11 HDAC isoforms was used to rationalize the observed biological results.

Keywords: Cross metathesis, histone deacetylases, lung cancer, epigenetics, molecular modeling

Human histone deacetylases (HDAC) and their inhibitors (HDACi) are part of the therapies used to treat human cancers, with four HDACi approved by FDA: SAHA 1(1) (suberoyl anilide hydroxamic acid, Chart 1, vorinostat) for cutaneous T-cell lymphomas (CTCL), belinostat 2(2) for relapsed or refractory peripheral T-cell lymphoma (PTCL), panobinostat 3 for multiple myeloma,3 and FK228 4(4) (romidepsin) for CTCL. Chidamide 5 (Tucidinostat) is approved only in China for PTCL.5 Nevertheless, solid tumor treatments with epigenetic compounds are still needed.6 HDACs participate in the regulation of gene expression by epigenetic mechanisms affecting chromatin structure and function.7 HDACs are a subgroup of 11 zinc-dependent proteins that deacetylate lysine residues of proteins including the core nucleosomal histones H3, H4, H2A, and H2B, leading in turn to the repression of gene expression. Some HDACs deacetylate nonhistone proteins, like HDAC6 for tubulin. HDACs are grouped in three classes, class I (HDAC1–3, 8), class II (IIa HDAC4, 5, 7, 9, and IIb HDAC6, 10), and class IV (HDAC11). The seven NAD-dependent sirtuins (SIRT1–7) represent the class III deacetylases. The overexpression of HDACs in cancer cell lines is correlated with the repressed expression of tumor suppressor genes (TSG),8−10 and HDACi are evaluated alone or in combination.11

Chart 1. Some HDAC Inhibitors Illustrate Cap/ZBGs Selectivity Profiles.

Chart 1

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HDACi are composed of a zinc-binding group (ZBG) linked by a carbon structure to a “cap” group, mostly aromatic,12 in interaction with the HDACs external solvent accessible surface. HDACi limitations’ are their pharmacokinetics, the side effects at the effective dosing and resistance,13 possibly avoided by systemic low dosing administration for a better renormalization of cancer cells.6 Bulk substituents and the absence of amide bonds may favor the plasma stability of hydroxamates14 in various species. The lack of selectivity of clinically approved HDACi limits their specific applications.15 The selectivity against class I HDACs results from para-substituted benzamide inhibitors,16 4-alkylaminomethylbenzhydroxamic acid scaffold, as in tubastatin or nexturastat, gives HDAC6 selectivity,17 whereas the trifluoromethyloxadiazole TMP-195 has HDAC7 selectivity.

Current compound design is focused on HDAC1–3, 4, 6, and 8 selective inhibitors due to a better biological knowledge. We previously validated cross metathesis (CM) to prepare alkyl-based hydroxamate and benzamide as HDACi.18 We present an extension with various ZBGs: hydroxamic acids, thiols, and benzamide as in SAHA, romidepsin, and chidamide. Other ZBG were not explored.19 We selected indole and naphthyl20 groups found as caps in HDACi. Indoles are known to be reluctant in CM reaction, but their presence reduces HDACi cardiac toxicity.21 A naphtoxy group instead of a naphthylamide may comply with better plasma stability. Despite its simplicity our naphthyl series was unknown but similar to a para-compound used to develop HDAC8 inhibitors with large cap groups.22

The alkene 8 was prepared from thiol 7 (Scheme 1) to complement our library ZBG-protected alkenes 5 and 6. A general TFA deprotection of the BOC and trityl groups was expected, with TES for the trityl one. The cap-bearing alkene 12 was prepared from naphthol 10. The CM reactivity of alkenes 8 and 12 was verified and gave compounds 9 and 13, respectively, in moderate to good yields. The CM between the ester 12 and the alkenes 5, 6, and 8 gave access, respectively, to three alkenes 14–16 in good isolated yields with our continuous injection protocol of Grubbs first generation catalyst. The Grubbs second generation catalyst was used for the benzamide 15. The possible dimers formed in each case were separated. Compounds 14–16 were reduced to compounds 17, 19, and 21, respectively, and deprotection gave the hydroxamate 18, benzamide 20, and thiol 22. The direct CM with free NH indole remains difficult (Scheme S1, Supporting Information) and was partly solved by the methylation of the amide 23 to give 24, still a poor substrate for CM, even with the Grubbs second generation catalyst, whatever the alkene used. In this series only the reduction of compound 27 to 29 worked, and the deprotection of 29 did not allow recovery of the expected benzamide. The conversion of compound 24 to a butenylcarboline may be evaluated in the future in CM. These difficulties with the indole series prompted us to focus on the naphthyl series for biological testing. As a summary, Grubbs I catalyst is well suited for thioalkenes and N,O diBoc hydroxamates. The Grubbs II catalyst must be preferred for the benzamide derivatives or other more reactive catalysts. The cap group should be apolar (Supporting Information, Table S1).

Scheme 1. Preparation of Cap- and ZBG-Bearing Alkenes, Validation, and Use in Cross Metathesis Reaction.

Scheme 1

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Reagents and conditions: (i) K2CO3, ACN, Br-(CH2)3-CH=CH2; (ii) Grubbs first generation catalyst, DCM, reflux, 6 + 1 h; (iii) CH3OH, H2SO4; (iv) K2CO3, DMF, Br-(CH2)3-CH=CH2; (v) second generation catalyst, DCM, reflux; (vi) H2, Pd/C, AcOEt; (vii) TFA, DCM; (viii) TFA/TES/DCM 1:0.1:1.

Compounds 18, 20, and 22 were tested for global HDAC inhibition using our BRET assays in living cells (Figure S1A–C, BRET principle, Supporting Information).23 SAHA (EC50 = 1.68 μM) and CI-994 (EC50 = 3.81 μM) were used as controls (Table 1; Figure S2A, Supporting Information) and gave results similar to previous studies.23,24 Compounds 18 and 20 were able to enter cells and to induce an increase of histone H3 acetylation, illustrated by an increase of the BRET signal. The absence of activity for thiol 22 may be due to the formation of a disulfide bridge as in psammaplins in the cellular environment. These experiments gave for the hydroxamate 18 an EC50 of 7.84 μM, and for the benzamides 20, an EC50 of 8.14 μM. Comparison of HDACi-induced BRET max values, obtained from dose–response experiments (Figure S2B, Supporting Information), showed that compound 18, SAHA, and CI-994 lead to similar maximal level of histone H3 acetylation, whereas compound 20 appeared significantly less active. The best HDACi 18 was further studied with SAHA and CI-994 as controls in dose escalation experiments (Figure S3, Supporting Information) for the simultaneous determination of viability (Table 2) and toxicity toward the selected cancer cells. These experiments demonstrated that all tested compounds decreased cancer cell viability through induction of toxicity (Figure S3, Supporting Information). The IC50 obtained for the various cancer cell lines used (Table 2) is coherent with the EC50 obtained using BRET assay (Table 1). Compound 18 is less toxic than SAHA (about 4-fold), and A549 cells are the least sensitive to this compound. We noticed a correlation between induction of histone H3 acetylation and toxicity. For compound 18, we determined HDAC and sirtuin selectively, using a standardized in vitro assay (Table 3; Figure S4, Supporting Information). At 10 μM concentration, compound 18 was able to partially inhibit HDAC classes I (HDAC1,2,3,8), IIb (HDAC6,10), and IV (HDAC11), and no inhibition was noticed for class IIa and class III. One hundred percent inhibition was obtained only for HDAC6 (class IIb). The dose–responses in vitro (Figure S4, Supporting Information) showed that compound 18 is selective for HDAC6 (IC50 = 95 nM, Table 3), about 10-fold less active for HDAC3, and 17- to 37-fold less for the other isoforms. The reference compound TSA was not selective, with better activity against HDAC HDAC1–3,6 and 10 than for other isoforms. The selective inhibition of HDAC6 prompted us to examine histone H3 and α-tubulin acetylation in malignant pleural mesothelioma (MPM, meso 163) and lung adenocarcinoma (ADCA, A549) cells by western-blot. SAHA was used as a control for the induction of histone H3, and α-tubulin acetylation and CI-994 for the only induction of histone H3 acetylation. In meso 163 cells (Figure 1A upper panels), SAHA and compound 18 induced a rapid and transitory histone H3 acetylation, whereas the benzamide CI-994 induced rapid and sustained histone H3 acetylation. The changes in histone H3 acetylation modulate the expression of a wide range of genes. In this study, we measured the mRNA level of E-cadherin, an “epitheloid status” marker of epithelial to mesenchymal transition (EMT),25 and the expression of two TSG was evaluated: Semaphorin-3F (Sema-3F), which reduces tumor angiogenesis and progression and is lost or reduced in lung cancers,26 and p21, which is involved in cell cycle.27

Table 1. EC50 for the Induction of Histone Acetylation Measured by BRET Assay in Met-5A Pleural Mesothelial Cellsa.

Cpd. 18 20 SAHA CI-994
EC50 (μM) 7.84 ± 0.18 8.14 ± 0.32 1.68 ± 0.19 3.81 ± 0.17
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a

EC50 values were determined using GraphPad Prism, Prism 6 for Windows, by curve fitting using a sigmoidal dose–response model. Values represent means ± standard error of at least three independent experiments.

Table 2. IC50 (μM) Values for Viability of Meso 163 and 13, A549, and ADCA72 Cell Lines Treated with 18, SAHA, and CI-994 (72 h)a.

Cpd. Meso 13 Meso 163 A549 ADCA 72
SAHA 3.79 ± 0.18 3.67 ± 0.17 4.12 ± 0.18 3.95 ± 0.23
CI-994 7.83 ± 0.19 15.77 ± 0.19 15.96 ± 0.19 3.90 ± 0.18
18 15.62 ± 0.12 15.86 ± 0.14 62.36 ± 0.18 15.72 ± 0.16
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a

IC50 values were determined using GraphPad Prism, Prism 6 for Windows, by curve fitting using a sigmoidal dose–response model. Values represent means ± standard error of at least three independent experiments.

Table 3. Inhibition Profile and Isoform Selectivity of Compound 18 Compared to Reference Compoundsa.

      IC50 (μM)
target % inhibition 18, 10 μM ref 18 ref
HDAC1 84,7 TSA 3.5 0.011
HDAC2 67,1 TSA 3.4 0.016
HDAC3 87,9 TSA 1.0 0.010
HDAC4 –4,8 TSA na 2.5
HDAC5 2,8 TSA na 1.6
HDAC6 104,1 TSA 0.095 0.022
HDAC7 –16,3 TSA na 0.98
HDAC8 93,1 TSA 1.6 0.79
HDAC9 –14,3 TSA na 5.1
HDAC10 82,3 TSA 1.6 0.040
HDAC11 57,2 b 6.6 5.2
sirtuin1 –2,6 c Nd 6.7
sirtuin2 –11,8 c Nd 17
sirtuin3 –8,2 d Nd 36
sirtuin6 –13,4 EX527    
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a

TSA, (S)-trichostatin A; b, scriptaid; c, suramin; d, niacinamide; na, not active; Nd, not determined; ref, reference compound.

Figure 1.

Figure 1

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Effect of compound 18 (20 μM), SAHA (2.5 μM), and CI-994 (10 μM) on (A) histone H3 and α-tubulin acetylation in MPM and lung ADCA cells. Meso 163 and A549 cells were treated with the compounds for 6 or 20 h. Histone H3 and α-tubulin acetylation were analyzed using western-blot. Left column indicates the molecular weight; and on (B) E-cadherin, Sema-3F, and P21 expression in MPM and lung ADCA cells. Meso 163 and A549 cells were treated with the compounds for 24 h. mRNA expression of E-cadherin, Sema-3F, and p21 was measured using real-time PCR. Results are means ± SEM of four independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 1B shows that compound 18, SAHA, and CI-994 induced the expression of E-cadherin and of both TSGs suggesting a beneficial effect on MPM and lung cancer cells. Like SAHA, compound 18 induced a sustained α-tubulin acetylation demonstrating its inhibitory effect on cytoplasmic HDAC6, coherent with its high HDAC6 inhibition activity.28 As expected, CI-994 did not increase α-tubulin acetylation according to the specific activity of benzamide on nuclear HDAC.29 In A549 cells (Figure 1A lower panels), similar results were obtained. The only difference with meso 163 cells was the sustained activity of SAHA and compound 18 on histone H3 acetylation over time.

Insight into the ligand positioning and binding modes of compound 18 into 11 metal-dependent HDAC isoforms was performed by molecular docking study. Docking simulations were able to reproduce the cocrystal inhibitor binding modes with RMSD values below 1.5 Å for each isoform and took into account the important interactions between hydroxamic acid derivatives in the active center of HDAC isoforms.30,31 The method was additionally validated by comparing the ChemScore Fitness Function (CSFF) calculated for (S)-TSA and compound 18 with their experimentally obtained IC50 values within each isoform.32

GOLD CSFF values calculated for ligand-specific HDAC were in good agreement with the experimental inhibitory profiles of (S)-TSA and compound 18 compared within the same isoform (Figures S5–S8 and Table S2, Supporting Information). Compound 18 chelates with the Zn2+ ion inside the HDAC binding pockets, except for the isoforms that belong to the HDAC class IIa (HDAC5/HDAC7 and HDAC9). The binding modes of compound 18 into active pockets of HDAC1 and both catalytic domains of HDAC6 (CDI and CDII) are presented in Figure 2 (other HDACs in Figures S9–S20 and Table S2, Supporting Information). HDAC6 CDII has a wider hydrophobic rim of the catalytic site (14.015 Å) comparing to the hydrophobic rim of HDAC1 (9.765 Å). Furthermore, the second argument for more favorable interaction of compound 18 with HDAC6 is a deeper active channel, which is less restricted for inhibitor access.32 The naphthalene moiety of compound 18 forms favorable π–π interaction with aromatic residue of Phe680 in HDAC6 CDII. In addition, π-sulfur interactions are formed between Met682 and naphthalene ring (Figure S14, Supporting Information). A bidentate binding mode was inspected for compound 18 inside the binding pocket of HDAC6, whereas the monodentate coordination was observed for the same compound in the active site of HDAC1. The high HDAC6 inhibitory potency of this compound could be explained by favorable interactions of the naphthalene CAP group with the side chains located in the outer rim of HDAC6 enzyme, as well as bidentate coordination with Zn2+ ion. Additionally, the higher HDAC6 potency of compound 18 may be also explained by the differences in the length of the active pockets. It is previously shown that the compounds with six carbon-spacer possess optimal distance between hydroxamic acid and CAP group for HDAC1 inhibitory activity.33 When the spacer of the HDAC1 inhibitor is longer than six carbons, it is less favorable to make the hydrophobic interactions to the solvent exposed entrance of the catalytic site. Compound 18 has an aliphatic linker constructed of eight carbon atoms, which may explain its selective HDAC6 inhibitory profile and less pronounced interactions with the side chains in the outer rim of class I HDACs. Domain-selective HDAC6 inhibitors studies30 prompted us to examine possible domain selective affinity for compound 18. We observed slightly different CSFF values calculated for (S)-TSA and compound 18 between HDAC6 catalytic domains (higher CSFF for CDI). To define whether the compound 18 possesses higher affinity for CDI of HDAC6 isoform, advanced structure based in silico and crystallographic studies should be performed, for the more precise determination of the ligand’s domain selectivity.

Figure 2.

Figure 2

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Comparative presentation of hydrophobic rim of the catalytic sites in HDAC1 homology model (A), crystal structure of human HDAC6 second catalytic domain (B), and first catalytic domain (C) with compound 18.

In conclusion, CM was successfully used to prepare rapidly with a generic method a series of alkyl-based HDAC inhibitors bearing the most common ZBGs, and one of them is an in vitro nanomolar selective HDAC6 inhibitor. The method can be adapted to inhibitors of other relevant biological targets. The methodology should be applicable in combinatorial strategies. Molecular docking rationalized the inhibition profile of compound 18, introducing for the first time analysis of both CD1 and CD2 domains of HDAC6. The biological interest of compound 18 was demonstrated, with an increased acetylation of histones and α-tubulin, associated with the stimulation of the expression of E-cadherin and TSGs such as SEMA3F and p21.

Experimental Procedures

All biologically tested compounds were 95%+ pure as determined by HPLC. Typical synthetic sequence illustrated for compound 18. DCM, dichloromethane; TFA, trifluoroacetic acid; TES, triethylsilane; EA, ethyl acetate; PE, petroleum ether; TEA, trimethylamine; ACN, acetonitrile.

Methyl (Z/E)-1-((8-((tert-butoxycarbonyl)((tert-butoxycarbonyl)oxy)amino)-8-oxooct-4-en-1-yl)oxy)-2-naphthoate 14. Grubbs catalyst (50 mg) in DCM (3 mL) was added over 6 h (0,5 mL/h rate) to a boiling solution of 5 (89 mg, 0.33 mmol) and 12 (208 mg, 0.66 mmol) in DCM (3 mL) and refluxed 1 h more. After cooling, the solvent was removed (vacuum) and purification (flash chromatography silica, PE/EA/TEA 99.5/0/0.5, 250 mL, 97/2.5/0.5, 1 L, 94.5/5/0.5, 1 L followed by preparative thin layer chromatography; PE/EA 97.5/2.5 and 95/5) gave 14 (88 mg, 48%) as an orange oil. 1H NMR (CDCl3) δ ppm: 1.53 (4s, 18H), 2.02 (m, 2H), 2.34 (m, 4H), 2.92 (m, 2H), 3.95 (3s, 3H), 4.12 (dt, 2H, J = 1.0, 6.6 Hz), 5.55 (m, 2H), 7.58 (m, 3H), 7.84 (m, 2H), 8.27 (dd, 1H, J = 6.49, 7.33 Hz). 13C NMR (CDCl3) δ ppm: 23.9, 27.4, 27.5, 27.9, 28.0, 29.05, 29.1, 30.1, 30.3, 30.4, 36.8, 52.2, 85.2, 86.0, 119.2, 123.4, 123.7, 126.4, 126.7, 127.8, 128.3, 128.8, 129.7, 130.2, 130.8, 136.7, 157.4, 166.9, 170.2. HRMS Calcd. for C30H39NNaO9 [M + Na]+: 580,2517, found 580.2524.

Methyl 1-((8-(hydroxyamino)-8-oxooctyl)oxy)-2-naphthoate 18. TFA (0.33 mL, 4 mmol) was added to a solution of 17 (84 mg, 0.15 mmol) in DCM, and the solution was stirred for 3 h. The crude mixture was diluted with EA and washed (saturated aqueous NaCl 3 × 5 mL). The combined aqueous extracts were neutralized (saturated aqueous NaHCO3, pH 7) and extracted (EA, 3 × 20 mL). The combined organic layers were dried (MgSO4) and concentrated under vacuum to yield 18 (20 mg, 36%) as an orange oil. 1H NMR (CDCl3) δ ppm: 1.33 (m, 4H), 1.52 (m, 4H), 1.85 (t, 2H, J = 7.4 Hz), 1.96 (t, 2H, J = 7.3 Hz), 3.89 (s, 3H), 4.05 (t, 2H, J = 6.5 Hz), 7.66 (m, 2H), 7.75 (s, 2H), 7.99 (dd, 1H, J = 6.1, 7.1 Hz), 8.19 (dd, 1H, J = 6.3, 7,2 Hz), 8.69 (s, 1H), 10.37(s, 1H). 13C NMR (CDCl3) δ ppm: 25.6, 25.9, 29.0, 29.1, 30.2, 32.7, 52.7, 76.4, 119.8, 123.5, 123.9, 126.7, 127.4, 128.5, 128.5, 129.0, 136.5, 156.6, 166.8, 169.6. HRMS Calcd. for C20H25NNaO5 [M + Na]+: 382.1625, found 382.1626.

Acknowledgments

Authors thank the Centre National de la Recherche Scientifique, University of Poitiers, COST Action CM1406, Professor Olaf Wiest group for providing us homology models of 11 HDAC isoforms (HDAC1–HDAC11) used for molecular docking study.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00440.

  • Synthesis, characterizations for all compounds, 1H/13C NMR spectra and HPLC data for compounds 18, 20, and 22, biological experiments, docking methods, and Figures S1–S20 (PDF)

  • PDB files (ZIP)

Author Contributions

The manuscript was written through contributions of all authors.

Regions Nouvelle Aquitaine and Pays de la Loire, Ligue Contre le Cancer: committees of Vendée and Charente-Maritime. D.A., K.N., and D.R. acknowledge the project (contract no. 172033) supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia.

The authors declare no competing financial interest.

Supplementary Material

ml8b00440_si_001.pdf (3.2MB, pdf)
ml8b00440_si_002.zip (1.3MB, zip)

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ml8b00440_si_001.pdf (3.2MB, pdf)
ml8b00440_si_002.zip (1.3MB, zip)

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