Rational ligand choice extends the SABRE substrate scope

Colell, Johannes F. P.; Logan, Angus W. J.; Zhou, Zijian; Lindale, Jacob R.; Laasner, Raul; Shchepin, Roman V.; Chekmenev, Eduard Y.; Blüm, Volker; Warren, Warren S.; Malcolmson, Steven J.; Theis, Thomas

doi:10.1039/d0cc01330g

Cited by 25 publications

(46 citation statements)

References 54 publications

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“…It is assumed that the relatively small polarization enhancement can be increased by using higher para -hydrogen concentrations, higher partial pressures, and optimal SABRE catalysts 40 . These modifications might drastically improve the enhancement.…”

Section: Resultsmentioning

confidence: 99%

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Jeong

Min

Chae

et al. 2020

Sci Rep

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Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies. Coronavirus pneumonia (COVID-19) is a serious respiratory infectious disease that has emerged recently. Patients with coronavirus infection demonstrate fever with body temperature exceeding 38 °C, and symptoms, such as dry cough, fatigue, dyspnea, difficulty in breathing, and frosted glass-like symptoms in the lungs 1. The disease is known to be highly transmittable without the occurrence of severe symptoms. The number of cases has reached over tens of millions worldwide. To overcome this pandemic, many researchers have started working on developing a vaccine. However, ongoing vaccine developments are estimated to take over a year before becoming available for public use. As a result, the global clinical community is attempting to repurpose existing drugs to tackle the COVID-19 crisis. Recently, several drugs that can inhibit specific functions of the virus have been proposed and tested as part of the latest clinical treatment approaches. These drugs include chloroquine and hydroxychloroquine. Although the role of these drugs in the treatment of COVID-19 is controversial, hydroxychloroquine is more soluble than chloroquine and produces relatively less toxic metabolites 2-4. Although chloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline) and hydroxychloroquine (2-[4-[(7-chloroquinolin-4-yl)amino]pentylethylamino]ethanol), which have been in clinical usage for the last seventy years, are drugs for the treatment of autoimmune disease, they are also used as antimalarial drugs. These compounds have recently been reported as potential broad-spectrum antiviral drugs for COVID-19 5 ; however, their benefits against COVID-19 are controversial, with no evident effect on hospitalized patients 6. From a molecular perspective, the...

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Section: Resultsmentioning

confidence: 99%

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Jeong

Min

Chae

et al. 2020

Sci Rep

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“…Many researchers have optimized the polarization transfer catalysts that are essential for SABRE hyperpolarization [9,12–22] . Nowadays, iridium catalysts based on N‐heterocyclic carbenes (NHCs) are typically used in preference to the phosphine containing catalysts used in early developments [23,24] .…”

Section: Methodsmentioning

confidence: 99%

“…Nowadays, iridium catalysts based on N‐heterocyclic carbenes (NHCs) are typically used in preference to the phosphine containing catalysts used in early developments [23,24] . Since then, the performance of NHC‐based catalysts has been optimized by using the steric and electronic properties of the NHC to tune substrate exchange kinetics [12,22] and relaxation effects [21] . Structural modifications of the SABRE catalyst have been used as a route to facilitate ligation, exchange, and hyperpolarization of sterically bulky substrates [12,19] or even to facilitate hyperpolarization in aqueous solvents [25] .…”

Section: Methodsmentioning

confidence: 99%

Reversible Hyperpolarization of Ketoisocaproate Using Sulfoxide‐containing Polarization Transfer Catalysts

et al. 2020

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The substrate scope of sulfoxide‐containing magnetisation transfer catalysts is extended to hyperpolarize α‐ketoisocaproate and α‐ketoisocaproate‐1‐[13C]. This is achieved by forming [Ir(H)2(κ2‐ketoisocaproate)(N‐heterocyclic carbene)(sulfoxide)] which transfers latent magnetism from p‐H2 via the signal amplification by reversible exchange (SABRE) process. The effect of polarization transfer field on the formation of enhanced 13C magnetization is evaluated. Consequently, performing SABRE in a 0.5 μT field enabled most efficient magnetisation transfer. 13C NMR signals for α‐ketoisocaproate‐1‐[13C] in methanol‐d4 are up to 985‐fold more intense than their traditional Boltzmann derived signal intensity (0.8 % 13C polarisation). Single crystal X‐ray diffraction reveals the formation of the novel catalyst decomposition products [Ir(μ‐H)(H)2(IMes)(SO(Ph)(Me)2)]2 and [(Ir(H)2(IMes)(SO(Me)2))2(μ‐S)] when the sulfoxides methylphenylsulfoxide and dimethylsulfoxide are used respectively.

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“…These results may be compared with an asymmetric, bidendate catalyst containing a Phox group (Phox = 2-(2- (diphenylphosphanyl)phenyl)-4,5-dihydrooxazole), which was recently developed for SABRE. [17] The hyperpolarization of substituted pyridines including 2-methylpyridine and 2-fluoropyridine was reported for the Phox based catalyst. Hyperpolarization was achieved without using a coligand, which was attributed to the reduced steric bulk of the ligand sphere.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the enhancement of pyridine, which in previous work was often used as a reference ligand for SABRE, was found to decrease considerably. [17] Other molecules that cannot bind to the SABRE catalyst directly may be hyperpolarized by a relayed polarization transfer process, which can occur through proton exchange from SABRE polarized amines in aprotic organic solvents, [18,19] or through another polarization transfer step when binding to a second metal complex. [20] The addition of a coligand to the SABRE reaction mixture can further enhance the polarization by stabilizing the polarization transfer complex, breaking its symmetry, assisting in the catalyst activation, or by other mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Spin Hyperpolarization of NH₂‐ and CH₃‐Substituted Pyridine and Pyrimidine Moieties by SABRE

2020

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Hyperpolarization of N-heterocycles with signal amplification by reversible exchange (SABRE) induces NMR sensitivity gains for biological molecules. Substitutions with functional groups, in particular in the ortho-position of the heterocycle, however, result in low polarization using a typical Ir catalyst with a bismesityl N-heterocyclic carbene ligand for SABRE, presumably due to steric hindrance. With the addition of allylamine or acetonitrile as coligands to the precatalyst chloro(1,5-cyclooctadiene)[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene] iridium, the 1 H signal enhancement increased in several substrates with ortho NH 2 substitutions. For example, for a proton in 2,4-diaminopyrimidine, the enhancement factors increased from À 7 � 1 to À 210 � 20 with allylamine or to À 160 � 10 with acetonitrile. CH 3 substituted molecules yielded maximum signal enhancements of À 25 � 7 with acetonitrile addition, which is considerably less than the corresponding NH 2 substituted molecules, despite exhibiting similar steric size. With the more electron-donating NH 2 substitution resulting in greater enhancement, it is concluded that steric hindrance is not the only dominant factor in determining the polarizability of the CH 3 substituted compounds. The addition of allylamine increased the signal enhancement for the 290 Da trimethoprim, a molecule with a 2,4-diaminopyrimidine moiety serving as an antibacterial agent, to À 70.

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Rational ligand choice extends the SABRE substrate scope

Abstract: Here we report on chelating ligands for Signal Amplification By Reversible Exchange (SABRE) catalysts that permit hyperpolarisation on otherwise sterically hindered substrates.

Cited by 25 publications

References 54 publications

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Reversible Hyperpolarization of Ketoisocaproate Using Sulfoxide‐containing Polarization Transfer Catalysts

Nuclear Spin Hyperpolarization of NH₂‐ and CH₃‐Substituted Pyridine and Pyrimidine Moieties by SABRE

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Rational ligand choice extends the SABRE substrate scope

Abstract: Here we report on chelating ligands for Signal Amplification By Reversible Exchange (SABRE) catalysts that permit hyperpolarisation on otherwise sterically hindered substrates.

Cited by 25 publications

References 54 publications

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates

Reversible Hyperpolarization of Ketoisocaproate Using Sulfoxide‐containing Polarization Transfer Catalysts

Nuclear Spin Hyperpolarization of NH2‐ and CH3‐Substituted Pyridine and Pyrimidine Moieties by SABRE

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Nuclear Spin Hyperpolarization of NH₂‐ and CH₃‐Substituted Pyridine and Pyrimidine Moieties by SABRE