Catalytic Hydrogenation of Cytotoxic Aldehydes Using Nicotinamide

Letter pubs.acs.org/acscatalysis

Catalytic Hydrogenation of Cytotoxic Aldehydes Using Nicotinamide Adenine Dinucleotide (NADH) in Cell Growth Media Anh H. Ngo, Miguel Ibañez, and Loi H. Do* Department of Chemistry, University of Houston, 4800 Calhoun Road, Houston, Texas 77004, United States S Supporting Information *

ABSTRACT: We demonstrate, for the first time, that pentamethylcyclopentadienyl (Cp*) iridium pyridinecarboxamidate complexes (5) can promote catalytic hydride transfer from nicotinamide adenine dinucleotide to aldehydes in pH 7.4 buffered cell growth media at 37 °C and in the presence of various biomolecules and metal ions. Stoichiometric hydride transfer studies suggest that the unique reactivity of 5, compared to other common Cp*Ir complexes, is at least in part due to the increased hydride transfer efficiency of its iridium hydride species 5-H. Complex 5 exhibits excellent reductase enzyme-like activity in the hydrogenation of cytotoxic aldehydes that have been implicated in a variety of diseases. KEYWORDS: transfer hydrogenation, biocatalysis, bioorthogonal chemistry, biomimetic, detoxification, iridium catalysis

A

benzaldehyde to benzyl alcohol, using NADH as the hydride donor. As shown in Figure 1, the reaction of benzaldehyde (1.0

n emerging frontier in chemical biology is the development of synthetic catalysts that can interface with biological systems, either directly in carrying out chemical transformations inside living organisms or indirectly through ex vivo modification of biomolecules.1,2 The former is more difficult to achieve, compared to the latter, because of the heterogeneous reaction environment in which the catalyst must operate. In recent years, remarkable progress has been made in expanding our repertoire of biocompatible metal-catalyzed reactions, which include alkene hydrogenation,3−6 azide− alkyne cycloaddition,7 carbamate cleavage,8−15 and C−C bond cross-coupling.16−19 These advances have made possible new research avenues to be pursued, such as the design of novel catalytic drugs2,20−22 or the creation of new biosynthetic methods. Transition-metal-mediated hydride transfer reactions are versatile methods to convert carbonyl to alcohol groups or vice versa.23 Catalysts based on iridium have even been shown to be active in the presence of both air and water.24−29 For example, Sadler and co-workers reported the use of an organometallic Ir complex to promote hydride transfer from the natural cofactor nicotinamide adenine dinucleotide (NADH) to pyruvate in methanol/water (1:9) under air;30 however, the iridium complex used in this study was not employed in catalytic amounts and the reactions were performed in the absence of common biological components and salts, which are often catalyst inhibitors. Inspired by the work described above, we proceeded to determine whether catalytic hydride transfer to organic acceptors could be achieved using a synthetic catalyst under physiologically relevant reaction conditions.31 To explore this possibility, we evaluated the competency of various pentamethylcyclopentadienyl (Cp*) iridium complexes to convert © XXXX American Chemical Society

Figure 1. Hydrogenation of benzaldehyde by complexes 1−9 using NADH as the hydride donor. Reaction conditions: benzaldehyde (0.05 mmol), NADH (0.06 mmol), metal complex or salt (1.0 μmol), tBuOH/PBS (2:8, 3 mL), 37 °C, 24 h. Yields were determined by gas chromatography (GC), using an internal standard.

equiv) and NADH (1.2 equiv) in tert-butanol and phosphatebuffered saline (PBS) (2:8) for 24 h at 37 °C gave little (≤20% yield) to no benzyl alcohol when complexes [Cp*Ir(2,2′bipyridine)(H2O)](SO3CF3)2 (1a),32 [Cp*Ir(6,6′-dihydroxy2,2′-bipyridine)(H 2 O)](SO 3 CF 3 ) 2 (1b), 3 3 [Cp*Ir(2phenylpyridine)Cl] (2), 34 [Cp*Ir(4-(1-pyrazoyl)benzoic acid)]2(SO4) (3),27 or [Cp*Ir(2,6-dicarboxylpyridine)Cl] (4)35 were tested as catalysts (2 mol %; see Chart 1). The Received: February 6, 2016 Revised: March 16, 2016

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ACS Catalysis Chart 1. Ir and Ru Complexes Tested in This Study

Figure 2. Hydrogenation of benzaldehyde by 5a/NADH in the presence of biologically relevant additives. Reaction conditions: benzaldehyde (0.06 mmol), NADH (0.12 mmol), 5a (0.6 μmol), tBuOH/PBS (2:8, 3 mL), 37 °C, 15 h. Yields were determined by GC using an internal standard. Abbreviations: GSH = glutathione, Cys = cysteine, Ade = adenine, Glu = glucose, Asc = ascorbic acid.

diiridium [Cp2*Ir2Cl2(4,4′,6,6′-tetrahydroxybipyrimidine)]Cl2 (6) 36 and monoruthenium [Ru(hexamethylbenzene)(phenanthroline)Cl]Cl (7)37 complexes were also found to be poor catalysts. To our surprise, when [Cp*Ir(N-phenyl-2pyridinecarboxamidate)Cl] (5a)38 was used instead, benzyl alcohol was obtained in ∼89% yield. Derivatives of 5a, containing either electron-withdrawing groups (e.g., chloro in 5b and nitro in 5c) or electron-donating groups (e.g., methoxy in 5d and methylthio in 5e) on the phenyl ring of the pyridinecarboxamidate ligand were also highly efficient catalysts (81%−91% yield). In contrast, the [Cp*IrCl2]2 (8) complex and IrCl3 salt (9) afforded only ∼11% and ∼0% benzyl alcohol, respectively. Similar results were obtained when sodium formate was used as the hydride donor, instead of NADH (see Figure S1 in the Supporting Information). Catalyst 5a was found to be robust and could be recycled for at least five times without any loss in catalytic activity (Figure S2 in the Supporting Information). Reaction optimization studies showed that the use of greater amounts of the hydride donors NADH or formate (up to ∼5−6 equiv, Figures S3 and S4 in the Supporting Information) led to greater yields of benzyl alcohol in less time. Reactions using NADH required longer reaction times, compared to those using sodium formate, which suggests that dehydrogenation of NADH by 5a to afford iridium-hydride species (Ir−H, vide inf ra) occurs more slowly than with sodium formate. To evaluate the tolerance of 5a toward common biomolecules, such as amino acids, nucleobases, carbohydrates, and organic cofactors, the reduction of benzaldehyde by 5a/ NADH was investigated in the presence of various additives (Figure 2). When using 1 mol % of 5a at 200 μM concentration, a good yield of benzyl alcohol was obtained in the presence of glucose (Glu, 5.0 mM, 77% yield) and ascorbic acid (Asc, 1.0 mM, 61%). Reactions performed using the nitrogenous base adenine (Ade, 1.0 mM) led to an appreciable decrease in yield (44%), compared to the control (72%). The presence of thiol-containing additives has the greatest inhibitory effect on 5a. At 0.05 mM of glutathione (GSH) ∼60% of benzyl alcohol was obtained, whereas at 1.0 mM of GSH only ∼3% of benzyl alcohol was obtained. The amino acid cysteine (Cys, 1.0 mM) also has a similar effect as GSH on 5a, giving only ∼16% of product. Cystine (the disulfide form of cysteine) does not exhibit any catalyst inhibitory effect, whereas N-acetyl cysteine showed moderate catalyst inhibition, but to a lesser degree,

compared to cysteine (data not shown). When the iridium catalyst loading was increased to 2 mol % at a concentration of ∼667 μM (Figure S5 in the Supporting Information), good conversion of benzaldehyde to benzyl alcohol was achieved (up to ∼73%), even in the presence of GSH (1.0 mM) or Cys (1.0 mM). The sensitivity of metal catalysts toward thiols and nucleobases is typically attributed to metal coordination inhibition.20,39 Ward and co-workers have shown that precious metal catalysts can be shielded from the detrimental effects of cellular components by attaching the catalyst to a protein scaffold and/or using thiol neutralizing chemical reagents. Similar strategies could be employed to enable the use of 5 under high concentrations of biological nucleophiles. When 5a (1 mol %) was tested in cell culture media, such as RPMI-1640 or M199, which typically have concentrations of GSH and other biological nucleophiles in the low micromolar concentration or below, reduction of benzaldehyde by NADH to benzyl alcohol occurred in ∼40%−50% yield after 15 h at 37 °C (Figure S6 in the Supporting Information). For comparison, many transition-metal catalysts that have been tested in cell culture media or cell lysate exhibit only modest activity at best1 (e.g., 14% conversion with a Ru complex,10 21% conversion with Pd nanoparticles16). The reduced activity of 5a in cell culture media, compared to that in PBS, is attributed to the catalyst poisoning effects of sulfur- and nitrogen-containing nucleophiles present in growth media. To determine whether transfer hydrogenation can be promoted by nonenzymatic species that are present in cells, we proceeded to screen the reaction of benzaldehyde and sodium formate in the presence of various biologically relevant metal ions (2 mol %, ∼667 μM in t-BuOH/HEPES 1:9), including transition metals (Cr2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and alkali/alkaline-earth metals (Na+, K+, Mg2+, Ca2+). Under the conditions explored, no benzyl alcohol was observed in the presence of metal salt additives (Figure S7 in the Supporting Information). Reactions using NADH instead of formate yielded similar results. Although it has been reported previously that Mg2+ could be used to promote hydride transfer from nicotinamide analogues to ketones,40 these reactions were conducted in acetonitrile rather than in aqueous media. Our 2638

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from the reaction between a metal catalyst with a hydride donor, followed by protonolysis or the delivery of the hydride to an organic acceptor.23 In our study, we wanted to ascertain whether the reactivity differences between the various classes of iridium complexes tested in Chart 1 were due to either the formation of Ir−H species from NADH or to hydride transfer from Ir−H to benzaldehyde (Scheme 1). We selected 1a, 2,

results suggest that transfer hydrogenation between NADH and aldehydes can be carried out selectively by 5 without undergoing side reactions with adventitious metal ions, thus achieving bioorthogonality. Next, we investigated the substrate scope of catalytic transfer hydrogenation by the Cp*Ir pyridinecarboxamidate complexes. The reactions were performed in the presence of an aldehyde or ketone (1.0 equiv), formate (2.0 equiv), and 0.5 mol % of 5a in t-BuOH/PBS (2:8 or 4:6) at 37 °C for 15 h (see Table 1).

Scheme 1. Transfer Hydrogenation by Iridium Complexes

Table 1. Hydrogenation of Aldehydes/Ketones Using 5a/ Formatea

and 5a as representative of complexes that have neutral N,N−, anionic C,N−, and anionic N,N− bidentate donors, respectively, to carry out these investigations. Each iridium complex (1.0 equiv) was combined with NADH (2.0 equiv) in a deoxygenated mixture of t-BuOH/D2O (7:3) or THF/D2O (7:3) and then sealed inside a J-Young tube. After 15 h at 37 °C, the 1H NMR spectra of all three samples showed peaks corresponding to the presence of new Ir−H species. The hydride signals for [Cp*Ir(2,2′-bipyridine)H]+ (1a-H),41 [Cp*Ir(2-phenylpyridine)H] (2-H),42 and [Cp*Ir(N-phenyl2-pyridinecarboxamidate)H] (5a-H) were observed at −11.5 (t-BuOH/D2O), −15.3 (THF/D2O), and −11.3 ppm (tBuOH/D2O) in their 1H NMR spectra (Figure S13 in the Supporting Information), respectively. Their assignments were confirmed by comparison to the spectra of authentic samples of the corresponding Ir−H complexes. Because 1a, 2, and 5a were all capable of generating Ir−H species from NADH, we postulated that their reactivity differences might be due to their hydride transfer efficiency. To test this hypothesis, we performed stoichiometric hydride transfer reactions between independently prepared iridium-hydride complexes and benzaldehyde. When either 1a-H or 2-H (1.0 equiv) was mixed with benzaldehyde (1.0−3.0 equiv) in a deoxygenated solution of CD3OD and allowed to react for 20 h at 37 °C, no hydride transfer occurred, as determined by 1H NMR spectroscopy (see Figures S14 and S15 in the Supporting Information). However, when 5a-H (1.0 equiv) and benzaldehyde (1.0 equiv) were combined under the same reaction conditions, after 15 h, quantitative conversion of benzaldehyde to benzyl alcohol occurred, as indicated by both NMR spectroscopic (see Figure 3, as well as Figure S16 in the Supporting Information) and gas chromatographic analyses of the reaction products (Figures S11 and S12 in the Supporting Information). These results are entirely consistent with the observation above, that 5a is an efficient hydride transfer catalyst, whereas 1a and 2 are not (Figure 1). A possible application of the Cp*Ir pyridinecarboxamidate complexes is in the catalytic degradation of cytotoxic compounds in vivo. Low-molecular-weight α,β-unsaturated aldehydes that are formed from lipid peroxidation, such as acrolein43 and 4-hydroxynon-2-enal,44,45 have been strongly implicated in a variety of metabolic diseases, neurodegenerative disorders, and cancers. Although enzymes such as glutathione stransferase, aldose reductase, and aldehyde dehydrogenase can metabolize cytotoxic aldehydes endogenously, patients with certain diseases typically exhibit low levels of these enzymes.45 Based on our iridium catalyst studies above, we propose that it

a

Conditions: aldehyde or ketone (0.06 mmol), formate (0.12 mmol), 5a (0.3 μmol), t-BuOH/PBS (2:8, 3.0 mL), 37 °C, 15 h. bYields were determined by GC analysis relative to an internal standard. Averaged from duplicate runs. See Figure S9 in the Supportign Information for the GC analyses. cTo improve substrate solubility, solutions containing t-BuOH/PBS (4:6) were used as solvent. dIsolated yield.

Benzaldehyde and its derivatives (entries 1−4) were reduced to their corresponding benzyl alcohols in excellent yields (>90%). The modest conversion of 2-naphthaldehyde to 2-naphthol (∼35% yield, entry 5) has been attributed to its poor solubility in t-BuOH/PBS. Aliphatic aldehydes (entries 6−10) were reduced to primary alcohols with moderate to good yields (∼54%−97%). Ketone-containing compounds are poor substrates. Neither acetophenone (entry 11) nor 4-heptanone (entry 13) was converted to its corresponding alcohol. Only the electron-deficient ketone 4′-nitroacetophenone (entry 12) was reduced, albeit in low yield (∼11%). These studies clearly indicate that there is a preference of the iridium-hydride (Ir− H) species, generated from 5a/formate, to react with aldehydes over ketones. Similar results were obtained when NADH was used instead of formate as the hydride source (see Table S1 in the Supporting Information). In transfer hydrogenation catalysis, the mechanism is believed to involve the generation of a metal-hydride species 2639

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iridium hydride species derived from 5 are more efficient hydride donors compared to other structurally similar Cp*Ir complexes. The origin of this unusual behavior is still an open question. We are currently investigating the hydricity of 5-H (ΔG H− ) as well as the possible involvement of the pyridineamidate ligand during catalysis. Most importantly, this work demonstrates that transfer hydrogenation catalysis is a versatile bioorthogonal reaction that can be exploited further in applications such as the catalytic detoxification of disease-causing agents.

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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/acscatal.6b00395. Synthesis and characterization and reaction summaries (PDF) X-ray crystallographic information for compounds in this study (CIF)

Figure 3. 1H NMR spectra (CD3OD, 500 MHz) of (A) complex 5aH, (B) complex 5a-H + benzaldehyde, 15 min, and (C) complex 5a-H + benzaldehyde, 15 h. Peaks corresponding to benzaldehyde (*) and benzyl alcohol (open circles, o) are labeled accordingly in the spectra.

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might be possible to utilize complex 5 as an enzyme mimic for aldehyde detoxification. Because the naturally occurring cofactor NADH can be employed as a hydride source, intracellular transfer hydrogenation would not require any external co-additives. To determine the feasibility of such an approach, we evaluated the reaction of 4-hydroxynon-2-enal (9, 1 equiv) with NADH (2.0 equiv) using 5a (1 mol %) in tBuOH/M199 (5:95) at 37 °C (Scheme 2). After 15 h, ∼94% of

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the University of Houston New Faculty Start-up for funding this work.

Scheme 2. Hydrogenation of 4-Hydroxynon-2-enal (9)a

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a Reaction conditions: 9 (0.06 mmol), NADH (0.12 mmol), 5a (0.6 μmol), t-BuOH/M199 (5:95, 3.0 mL), 37 °C, 15 h. Yields were determined by GC using an internal standard (see Figure S10 in the Supporting Information).

9 was converted to 4-hydroxynon-2-en-1-ol (10, 88%) and 4hydroxynonan-1-ol (11, 6%). Increasing the reaction time (>24 h) led to higher ratios of 11:10, which suggests that hydrogenation occurs at the aldehyde group prior to hydrogenation of the double bond. Similar results were obtained when t-BuOH/RPMI-1640 was used as solvent (Figure S8 in the Supporting Information). The high efficiency of this reaction in cell growth media suggests that 5a is an excellent candidate for further studies inside live cells, which is the focus of our future work. In summary, our investigations revealed that Cp*Ir pyridinecarboxamidate complexes are capable of mediating catalytic hydride transfer from either NADH or formate to aldehydes in PBS buffer and cell culture media. The iridium catalysts are tolerant of up to moderate concentrations of biological nucleophiles, including thiols such as glutathione and cysteine. Stoichiometric hydride transfer studies showed that 2640

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