Communication pubs.acs.org/Organometallics
Selective Photorelease of an Organometallic-Containing Enzyme Inhibitor Anna Leonidova, Cristina Mari, Christine Aebersold, and Gilles Gasser* Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland S Supporting Information *
ABSTRACT: Histone deacetylases (HDACs) are regarded as promising targets in cancer and a growing number of other diseases due to their crucial involvement in epigenetics and cellular signaling. Many organic HDAC inhibitors are known, and several efficient metal-based analogues have been recently developed. Many of them contain a hydroxamic acid group that binds to the catalytic HDAC zinc center. In this work, a lightactivatable organometallic HDAC inhibitor (p-Fc-SAHA) was synthesized and characterized. More specifically, the hydroxamic acid moiety of a known ferrocene-containing HDAC inhibitor (Fc-SAHA) was blocked with a photolabile protecting group (PLPG), namely, 1-(bromomethyl)-4,5-dimethoxy-2nitrobenzene. Upon UV-A (350 nm) irradiation, Fc-SAHA could be successfully released from p-Fc-SAHA. Importantly, p-Fc-SAHA was significantly less active on HDAC1, HDAC2, and HDAC6 than Fc-SAHA. As expected, the inhibition activity of Fc-SAHA was recovered upon light irradiation. To our knowledge, this is the first study presenting the selective photorelease of an organometallic enzyme inhibitor.
H
clinics.4 However, clinical trials have also shown that HDAC inhibitors had low efficiency against solid tumors and severe side effects, particularly cardiotoxicity.5 Therefore, both novel inhibitors and targeted delivery approaches are being greatly sought.5a Over the last years, numerous metal complexes have been identified as excellent enzyme inhibitors.6 Several metal-based HDAC inhibitors have also been prepared by combining a known organic pharmacophore with platinum anticancer drugs,7 ferrocene,8 ferrocifen,9 ReCp(CO)310 (Cp = cyclopentadienyl), and Ru(II) polypyridyl moieties.11 Most of these compounds have efficiently inhibited HDACs and shown to be highly cytotoxic toward various cancer cell lines. Polypyridyl Ir(III) and gold(III) porphyrin HDAC inhibitors have also been reported.12 In this work, we sought to design a metal-based HDAC inhibitor whose activity could be controlled by light irradiation. To this end, the crucial interactions of the inhibitor with an HDAC catalytic site had to be blocked by a photolabile protecting group (PLPG). Such a “caging” technique has been widely applied to organic molecules and metal ions to understand biological processes and to achieve light-activatable drug release.13 Our group has, for example, demonstrated that cytotoxic metal complexes as well as an organic enzyme inhibitor could be reactivated upon light irradiation.14 Similarly to photodynamic therapy (PDT), this technique allows for
istone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues of cellular proteins. Deacetylation of HDACs’ main targethistonesleaves the histone core positively charged and thus permits DNA to coil tightly around it.1 In addition, these enzymes can act on many nonhistone proteins, such as α-tubulin, importin-α, nuclear receptors, and transcription factors.2 The resulting transcriptional repression, modulation of signaling pathways, cellular architecture, and nuclear import make HDACs one of the key enzymes not only in cancer but also in metabolic syndromes and neurodegenerative and inflammatory diseases.3 HDAC inhibitors are thereby highly attractive drug candidates, and vorinostat (SAHA, suberoylanilidehydroxamic acid, Scheme 1A) and depsipeptide (romidepsine) have already been approved against cutaneous T-cell lymphoma (CTCL) in Scheme 1. (A) Structures of SAHA and Fc-SAHA; (B) Synthesis of Caged Fc-SAHA Derivative (p-Fc-SAHA)a
a
Received: January 14, 2016
(i) KOH, EtOH/H2O, 80 °C, yield 37%. © XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.6b00029 Organometallics XXXX, XXX, XXX−XXX
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Organometallics
processes led to this amide byproduct. N−O bond homolysis followed by disproportionation predominates at shorter wavelengths, while at longer wavelengths it rather results from an alternative degradation of the aci-nitro intermediate of the photorelease pathway.20 Of note, a study on ferrocifenSAHA hybrids has found amide derivatives considerably cytotoxic despite their low impact on HDAC activity.9b Upon light irradiation of p-Fc-SAHA, five additional minor byproducts were clearly observed by LC-MS, but their structures could not be elucidated. From the studies on photorelease of benzohydroxamic acid and other photocaged compounds, five other byproducts can in fact be expected.14d,e,20,21e A carboxylic acid analogue of Fc-SAHA (see Figure S5) could be formed via a T1 reaction with oxygen in solution.20 In addition, the onitrobenzyl PLPG moiety of p-Fc-SAHA is supposed to rearrange into its 2-nitrosobenzaldehyde and 2-nitrobenzaldehyde (Figure S5) forms. Corresponding alcoholsprobably resulting from the alkoxy radical (N−O cleavage) abstracting hydrogen from solvent moleculesare also possible byproducts (Figure S5). After having established that p-Fc-SAHA could indeed photorelease the intact Fc-SAHA, the HDAC inhibition properties of p-Fc-SAHA were tested in the dark and upon UV-A irradiation (10 min, 2.79 J/cm2). The irradiation dose was chosen so as to uncage over 80% of Fc-SAHA, yet cause no harm in vitro.14d Ferrocene-SAHA hybrids have been reported to possess relatively broad HDAC inhibitory profiles, affecting class I and IIb enzymes.8a As the derivative chosen for this study has already shown excellent inhibition activity toward HDAC1, HDAC2, and HDAC6, these three enzymes were used to evaluate p-Fc-SAHA as well. As shown in Table 1 (and
spatial and temporal control of the activity of the system. At the same time, it circumvents the dependence on oxygen, which is often scarce at the internal core of generally hypoxic tumors.15 This concept, relying on the use of light to activate a cytotoxic compound without the need of oxygen, is often referred to as photoactivated chemotherapy (PACT).16 Of note, in the context of this work, it is worth mentioning the work of Kodanko and co-workers, who used Ru(II) complexes to release organic enzyme inhibitors upon light irradiation.17 In this Communication, we present, to the best of our knowledge, the first specific light-controlled release of an organometallic enzyme inhibitor. For this proof-of-concept study, we have chosen one of the first metal-basedand, above all, light-stableHDAC inhibitors reported, namely, a ferrocene derivative of SAHA (FcSAHA) (Scheme 1A).8a This series of inhibitors is based on the replacement of SAHA’s aryl cap with a ferrocene moiety. Their mechanism of action is thought to be similar to that of SAHA. While the aryl/ferrocene group fits into a hydrophobic pocket, the alkyl chain allows for the hydroxamic acid to bind to the catalytic zinc.8a,18 Structure−activity relationship (SAR) studies on SAHA derivatives have demonstrated that the addition of steric bulk in close proximity to the hydroxamic acid severely decreased HDACs’ inhibition.18b,c Fc-SAHA was prepared following a previously published procedure.8a Its hydroxamic acid group was then successfully photocaged with the 1-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene PLPG via a nucleophilic substitution (Scheme 1B). Reaction conditions were adapted from those reported for the synthesis of organic hydroxamates19 and the photocaging of benzohydroxamic acid.20 The formation and purity of the photocaged Fc-SAHA (p-Fc-SAHA) was confirmed by LC-MS analysis and 1H and 13C NMR spectroscopy (Figures S1−S3). As shown in Figure S3, a single peak in the UV trace of the LCMS of p-Fc-SAHA was observed. A single peak with an m/z 643.4 corresponding to [M]+ was, as expected, detected. 1H and 13C NMR spectra (Figures S1 and S2) show the appearance of the expected additional peaks of the photolabile moiety: the CH2 link (2H at 5.28 ppm, C at 74.8 ppm), the two OMe groups (2 × 3H at 4.02 and 3.98 ppm, 2C at 57.2 and 57.0 and ppm), and the benzene ring (2H 7.74 and 7.54 ppm, 6C at 154.7, 149.4, 141.3, 128.8, 112.5, and 109.1 ppm). Following the isolation of the caged organometallic enzyme inhibitor, the next step in this study was to assess if it could be indeed released upon light irradiation. For this purpose, p-FcSAHA was irradiated in a UV reactor (300−400 nm range, centered at 350 nm) to evaluate its photorelease kinetics and byproduct formation. Hydroxamic acids, N,O-diacylhydroxylamines, and N-alkylbenzohydroxamates themselves are known to undergo N−O bond homolysis upon UV irradiation.21 The photorelease studies on benzohydroxamic acid caged with a simple o-nitrobenzyl PLPG have demonstrated that N−O bond cleavage was indeed taking place.20 However, the released benzohydroxamic acid was still the major product, particularly favored at longer irradiation wavelengths (340 vs 254 nm). In our case, LC-MS performed after 10 min of irradiation (2.79 J/ cm2) (Figure S4) showed that the major peak corresponded indeed to the intact Fc-SAHA (m/z 448.2). One of the byproducts of N−O bond cleavage, namely, an amide analogue of Fc-SAHA (Figure S5), was also detected (m/z 432.2) in an approximately 1:9 ratio to Fc-SAHA (assuming a similar absorption coefficient at 270 nm). In the case of benzohydroxamic acid, it has been suggested that two different
Table 1. IC50 of SAHA, Fc-SAHA, and p-Fc-SAHA in the dark and p-Fc-SAHA after UV-A Irradiation (10 min, 2.79 J/ cm2) IC50 (μM) compound SAHA Fc-SAHA p-Fc-SAHA p-Fc-SAHA + UV
HDAC1 0.09 0.13 3.45 0.11
± ± ± ±
0.01 0.06 0.77 0.01
HDAC2 0.20 0.33 > 10 (209 0.23
± ± ± ±
HDAC6 0.06 0.06 71)a 0.03
0.05 0.03 10 0.04
± ± ± ±
0.01 0.01 2a 0.05
a
IC50 is out of the experimental concentration range, estimated by extrapolation.
Figures S8−10), our results for Fc-SAHA alone are consistent with the previously published data. SAHA and Fc-SAHA possessed similar enzyme inhibition profiles, with the lowest IC50 observed for the class IIb HDAC6.8a The photocaged analogue, p-Fc-SAHA, on the other hand, was from 30 to over 600 times less active. The remaining effect of p-Fc-SAHA in the higher micromolar range could be due to the insufficient steric bulk of the PLPG used. In fact, a small internal cavity just below the active site has been identified for some HDACs by X-ray crystallography.18a,d−f The PLPG of p-Fc-SAHA could still be small enough to fit into this cavity, allowing for weak hydroxomate/zinc interactions. A bulkier PLPG might thereby improve the light/dark activity ratio. Importantly, UV-A irradiation fully restored the HDAC inhibition activity of pFc-SAHA. In conclusion, this study demonstrates the possibility of designing an efficient light-controlled organometallic HDAC inhibitor. Although insufficient aqueous solubility of p-FcB
DOI: 10.1021/acs.organomet.6b00029 Organometallics XXXX, XXX, XXX−XXX
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Organometallics
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SAHA has prevented us from accurately assessing its behavior in cell culture, the HDAC inhibition results are highly encouraging. Further studies will focus on the optimization of the PLPG moiety and the addition of targeting vectors to further increase light/dark activity ratio and specificity toward cancer tissues, respectively.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.6b00029. Experimental procedures, characterization spectra, enzyme inhibition (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Fax: +41 44 635 6803. Tel: +41 44 635 4630; www: www.gassergroup.com. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the Swiss National Science Foundation (SNSF Professorship PP00P2_133568 as well as Research Grants Nos. 200021_129910 and 200020_146776 to G.G.), the University of Zurich (G.G.), the Stiftung für Wissenschaftliche Forschung of the University of Zurich (G.G.), and the Forschungskredit of the University of Zurich (Grant K-73532-01-01 to C.M.).
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