Applications of Hydrolases in Medicinal Chemistry

A special issue of Catalysts (ISSN 2073-4344). This special issue belongs to the section "Biocatalysis".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 19406

Special Issue Editors


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Guest Editor
Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
Interests: lipases; stereoselective biocatalysis; enantiomeric APIs

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Guest Editor
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
Interests: biocatalysis; enzyme promiscuity

Special Issue Information

Dear Colleagues,

The implementation of practical, efficient, atom economical, cost-efficient, scalable and environmentally friendly synthetic methods that enable the rapid preparation of pharmacologically relevant compounds in high chemical and optical purity as well as yields close to quantitative values is of critical interest not only to academic researchers, but particularly to chemists who are responsible for designing industrial or manufacturing syntheses.

In this context, biocatalytic processes based on hydrolases are the method of choice since these relatively inexpensive biocatalysts exhibit mostly excellent regio-, chemo- and enantio-selectivity as well as remarkable catalytic activity even in low-water environments including nearly anhydrous organic solvents, without needing the addition of costly external acceptors and cofactors (NAD(P)H, FADH2, etc.). Since the 1980s hydrolases have become well-anchored catalysts in plethora of synthetic endeavors and industrial applications, being some of the most common biocatalysts currently in use in organic chemistry. The prestigious status of hydrolases mainly stems from their ability to play an irreplaceable role in chirality inducement, high operational stability under non-physiological conditions, and wide commercial availability in both native and immobilized forms. Hydrolase-based biotransformations have shown to be superior compared to traditional chemical synthesis approaches, especially in C–O functional group chemistry of chiral secondary alcohols and their respective esters. Moreover, thanks to the advantageous structural flexibility of hydrolases, enzymes of this type are also prone to catalyze both the transformation of a wide spectrum of unnatural substrates of highly functionalized structures as well as reactions which are far from their “physiological repertoire”. The so-called “enzyme promiscuity” of hydrolases (in particular lipases) experimentally proven in various types of condensations (cross-aldol, aza-Michael, Morita–Baylis–Hillman, Knoevenagel, Henry-nitroaldol, Phillips etc.), multicomponent reactions (Biginelli, Hantzsch, Mannich, Ugi, Kabachnik–Fields etc.), and many other processes including oxidations (epoxidation of alkenes, Baeyer–Villiger etc.), domino thia-Michael–Henry or Suzuki–Miyaura reactions showed that these enzymes are also valuable biocatalysts in C–C and/or C–heteroatom bond formations. All the abovementioned unique features of hydrolases make it so that these biocatalysts are willingly applied in the synthesis of high-added-value compounds with controlled stereochemical properties, such as pharmaceuticals, agrochemicals, vitamins, flavors and fragrances or bulk products, including nutraceuticals, detergents, cosmetics, biofuels and biodegradable polymers.

We highly encourage potential authors to submit their manuscripts reporting on chemoenzymatic methods for the synthesis of novel compounds of defined biological activities, pharmacologically important chiral building blocks and/or generic active pharmaceutical ingredients (APIs) of known drugs.

Dr. Paweł Borowiecki
Dr. Dominik Koszelewski
Guest Editors

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Published Papers (8 papers)

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Research

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20 pages, 4219 KiB  
Article
Rational Design of a Biocatalyst Based on Immobilized CALB onto Nanostructured SiO2
by Carlos R. Llerena Suster, María V. Toledo, Silvana R. Matkovic, Susana R. Morcelle and Laura E. Briand
Catalysts 2023, 13(3), 625; https://doi.org/10.3390/catal13030625 - 20 Mar 2023
Cited by 2 | Viewed by 1295
Abstract
The adsorption of the lipase B from Candida antarctica (CALB) over nanostructured SiO2 (Ns SiO2 from now on) with and without the addition of polyols (sorbitol and glycerol) was investigated. The isotherms of adsorption made it possible to establish that the [...] Read more.
The adsorption of the lipase B from Candida antarctica (CALB) over nanostructured SiO2 (Ns SiO2 from now on) with and without the addition of polyols (sorbitol and glycerol) was investigated. The isotherms of adsorption made it possible to establish that the maximum dispersion limit was 0.029 µmol of protein per surface area unit of Ns SiO2 (29.4 mg per 100 mg of support), which was reached in 30 min of exposure. The studies through SDS-PAGE of the immobilization solutions and infrared spectroscopy of the prepared solids determined that CALB (from a commercial extract) is selectively adsorbed, and its secondary structure distribution is thus modified. Its biocatalytic activity was corroborated through the kinetic resolution of rac-ibuprofen. Conversions of up to 70% and 52% enantiomeric excess toward S-ibuprofen in 24 h of reaction at 45 °C were achieved. The biocatalytic performance increased with the increase in protein loading until it leveled off at 0.021 µmol.m−2, reaching 0.6 µmol.min−1. The biocatalyst containing the lipase at the maximum dispersion limit and co-adsorbed polyols presented the best catalytic performance in the kinetic resolution of rac-ibuprofen, an improved thermal resistance (up to 70 °C), and stability under long-term storage (more than 2 years). Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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17 pages, 2195 KiB  
Article
Scalability of U-Shape Magnetic Nanoparticles-Based Microreactor–Lipase-Catalyzed Preparative Scale Kinetic Resolutions of Drug-like Fragments
by Fausto M. W. G. Silva, Ali O. Imarah, Orsolya Takács, László Tuba and László Poppe
Catalysts 2023, 13(2), 384; https://doi.org/10.3390/catal13020384 - 10 Feb 2023
Cited by 2 | Viewed by 1543
Abstract
The production of active pharmaceutical ingredients (APIs) and fine chemicals is accelerating due to the advent of novel microreactors and new materials for immobilizing customized biocatalysts that permit long-term use in continuous-flow reactors. This work studied the scalability of a tunable U-shape magnetic [...] Read more.
The production of active pharmaceutical ingredients (APIs) and fine chemicals is accelerating due to the advent of novel microreactors and new materials for immobilizing customized biocatalysts that permit long-term use in continuous-flow reactors. This work studied the scalability of a tunable U-shape magnetic nanoparticles (MNPs)-based microreactor. The reactor consisted of a polytetrafluoroethylene tube (PTFE) of various inner diameters (ID = 0.75 mm, 1.50 mm, or 2.15 mm) and six movable permanent magnets positioned under the tube to create reaction chambers allowing the fluid reaction mixture to flow through and above the enzyme-loaded MNPs anchored by permanent magnets. The microreactors with various tube sizes and MNP capacities were tested with the preparative scale kinetic resolution of the drug-like alcohols 4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-2-ol (±)-1a and 4-(3,4-dihydroquinolin-1(2H)-yl)butan-2-ol (±)-1b, utilizing Lipase B from Candida antarctica immobilized covalently onto MNPs, leading to highly enantioenriched products [(R)-2a,b and (S)-1a,b]. The results in the U-shape MNP flow reactor were compared with reactions in the batch mode with CaLB-MNPs using similar conditions. Of the three different systems, the one with ID = 1.50 mm showed the best balance between the maximum loading capacity of biocatalysts in the reactor and the most effective cross-section area. The results showed that this U-shaped tubular microreactor might be a simple and flexible instrument for many processes in biocatalysis, providing an easy-to-set-up alternative to existing techniques. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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9 pages, 1925 KiB  
Article
Chemoenzymatic Protocol for the Synthesis of Enantiopure β-Blocker (S)-Bisoprolol
by Lucas Bocquin and Elisabeth Egholm Jacobsen
Catalysts 2023, 13(1), 54; https://doi.org/10.3390/catal13010054 - 27 Dec 2022
Cited by 2 | Viewed by 1989
Abstract
The β-blocker (S)-bisoprolol hemifumarate has been synthesised in 96% enantiomeric excess with 19% total yield in a six-step synthesis. A transesterification reaction of the racemic chlorohydrin 1-chloro-3-(4-((2-isopropoxyethoxy)methyl)phenoxy)propan-2-ol catalysed by lipase B from Candida antarctica resulted in the R-chlorohydrin in [...] Read more.
The β-blocker (S)-bisoprolol hemifumarate has been synthesised in 96% enantiomeric excess with 19% total yield in a six-step synthesis. A transesterification reaction of the racemic chlorohydrin 1-chloro-3-(4-((2-isopropoxyethoxy)methyl)phenoxy)propan-2-ol catalysed by lipase B from Candida antarctica resulted in the R-chlorohydrin in high enantiomeric purity. Reaction of this building block with isopropylamine in methanol gave (S)-bisoprolol, and further reaction with fumaric acid gave (S)-bisoprolol fumarate in 96% ee. Specific rotation value confirmed the absolute configuration of the enantiopure drug. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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12 pages, 1845 KiB  
Article
Chemo-Enzymatic Synthesis of Enantiopure β-Antagonist (S)-Betaxolol
by Susanne Hansen Troøyen and Elisabeth Egholm Jacobsen
Catalysts 2022, 12(12), 1645; https://doi.org/10.3390/catal12121645 - 15 Dec 2022
Cited by 1 | Viewed by 1279
Abstract
The β-blocker (S)-betaxolol has been synthesized in 99% enantiomeric excess (ee) from the commercially available precursor 4-(2-hydroxyethyl)phenol. The racemic chlorohydrin 1-chloro-3-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)propan-2-ol was esterified with vinyl acetate catalyzed by lipase B from Candida antarctica, which gave the R-chlorhydrin [...] Read more.
The β-blocker (S)-betaxolol has been synthesized in 99% enantiomeric excess (ee) from the commercially available precursor 4-(2-hydroxyethyl)phenol. The racemic chlorohydrin 1-chloro-3-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)propan-2-ol was esterified with vinyl acetate catalyzed by lipase B from Candida antarctica, which gave the R-chlorhydrin (R)-1-chloro-3-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)propan-2-ol in 99% ee with 38% yield. The enantiomeric excess of the R-chlorohydrin was retained in an amination reaction with isopropylamine in methanol to yield (S)-betaxolol in 99% ee and with 9% overall yield. We are under way to improve the yield. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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23 pages, 3532 KiB  
Article
Chemoenzymatic Synthesis of Optically Active Alcohols Possessing 1,2,3,4-Tetrahydroquinoline Moiety Employing Lipases or Variants of the Acyltransferase from Mycobacterium smegmatis 
by Beata Zdun, Izabela Kopińska, Maciej Dranka, Tamara Reiter, Wolfgang Kroutil and Paweł Borowiecki
Catalysts 2022, 12(12), 1610; https://doi.org/10.3390/catal12121610 - 8 Dec 2022
Cited by 1 | Viewed by 3377
Abstract
The enzymatic kinetic resolution (EKR) of racemic alcohols or esters is a broadly recognized methodology for the preparation of these compounds in optically active form. Although EKR approaches have been developed for the enantioselective transesterification of a vast number of secondary alcohols or [...] Read more.
The enzymatic kinetic resolution (EKR) of racemic alcohols or esters is a broadly recognized methodology for the preparation of these compounds in optically active form. Although EKR approaches have been developed for the enantioselective transesterification of a vast number of secondary alcohols or hydrolysis of their respective esters, to date, there is no report of bio- or chemo-catalytic asymmetric synthesis of non-racemic alcohols possessing 1,2,3,4-tetrahydroquinoline moiety, which are valuable building blocks for the pharmaceutical industry. In this work, the kinetic resolution of a set of racemic 1,2,3,4-tetrahydroquinoline-propan-2-ols was successfully carried out in neat organic solvents (in the case of CAL-B and BCL) or in water (in the case of MsAcT single variants) using immobilized lipases from Candida antarctica type B (CAL-B) and Burkholderia cepacia (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT) as the biocatalysts and vinyl acetate as irreversible acyl donor, yielding enantiomerically enriched (S)-alcohols and the corresponding (R)-acetates with E-values up to 328 and excellent optical purities (>99% ee). In general, higher ee-values were observed in the reactions catalyzed by lipases; however, the rates of the reactions were significantly better in the case of MsAcT-catalyzed enantioselective transesterifications. Interestingly, we have experimentally proved that enantiomerically enriched 1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-2-ol undergoes spontaneous amplification of optical purity under achiral chromatographic conditions. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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21 pages, 2622 KiB  
Article
Resolution of Racemic Aryloxy-Propan-2-yl Acetates via Lipase-Catalyzed Hydrolysis: Preparation of Enantiomerically Pure/Enantioenriched Mexiletine Intermediates and Analogs
by Ana Caroline Lustosa de Melo Carvalho, Bruna Rocha de Oliveira, Gledson Vieira Lima, Jonatas Martins Negreiro, Maria Conceição Ferreira Oliveira, Telma Leda Gomes de Lemos, Marcos Reinaldo da Silva, Thiago de Sousa Fonseca, Rayanne Mendes Bezerra, Jose Cleiton Sousa dos Santos, Luciana Rocha Barros Gonçalves, Nathalia Saraiva Rios, Geancarlo Zanatta and Marcos Carlos de Mattos
Catalysts 2022, 12(12), 1566; https://doi.org/10.3390/catal12121566 - 2 Dec 2022
Cited by 4 | Viewed by 1591
Abstract
The lipase kinetic resolution (KR) of aryloxy-propan-2-yl acetates, via hydrolysis, produced enantiomerically pure/enantioenriched mexiletine intermediates and analogs. Racemic acetates rac-1-(2,6-dimethylphenoxy)propan-2-yl acetate (rac-5a), rac-1-(2,4-dimethylphenoxy)propan-2-yl acetate (rac-5b), rac-1-(o-tolyloxy)propan-2-yl acetate (rac- [...] Read more.
The lipase kinetic resolution (KR) of aryloxy-propan-2-yl acetates, via hydrolysis, produced enantiomerically pure/enantioenriched mexiletine intermediates and analogs. Racemic acetates rac-1-(2,6-dimethylphenoxy)propan-2-yl acetate (rac-5a), rac-1-(2,4-dimethylphenoxy)propan-2-yl acetate (rac-5b), rac-1-(o-tolyloxy)propan-2-yl acetate (rac-5c) and rac-1-(naphthalen-1-yloxy)propan-2-yl acetate (rac-5d) were used as substrates. A preliminary screening (24 h, phosphate buffer pH 7.0 with 20% acetonitrile as co-solvent, 30 °C and enzyme:substrate ratio of 2:1, m:m) was carried out with twelve lipases using acetate 5a as substrate. Two enzymes stood out in the KR of 5a, the Amano AK lipase from Pseudomonas fluorescens and lipase from Thermomyces lanuginosus (TLL) immobilized on Immobead 150. Under these conditions, both the (R)-1-(2,6-dimethylphenoxy)propan-2-ol [(R)-4a] and the remaining (S)-1-(2,6-dimethylphenoxy)propan-2-yl acetate [(S)-5a] were obtained with enantiomeric excess (ee) > 99%, 50% conversion and enantiomeric ratio (E) > 200. The KR study was expanded to racemic acetates 5b-d, leading to the corresponding chiral remaining acetates with ≥95% ee, and the alcohols 4b-d with ≥98% ee, and conversion values close to 50%. The best conditions for KRs of rac-5b-d involved the use of lipase from P. fluorescens or TLL immobilized on Immobead 150, 24 or 48 h and 30 °C. These intermediates had their absolute configurations determined using 1H NMR spectroscopy (Mosher’s method), showing that the KRs of these acetates obeyed the Kazlauskas’ rule. Molecular docking studies corroborated the experimental results, indicating a preference for the hydrolysis of (R)-5a-d. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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20 pages, 4046 KiB  
Article
Expanding Access to Optically Active Non-Steroidal Anti-Inflammatory Drugs via Lipase-Catalyzed KR of Racemic Acids Using Trialkyl Orthoesters as Irreversible Alkoxy Group Donors
by Beata Zdun, Piotr Cieśla, Jan Kutner and Paweł Borowiecki
Catalysts 2022, 12(5), 546; https://doi.org/10.3390/catal12050546 - 17 May 2022
Cited by 3 | Viewed by 3290
Abstract
Studies into the enzymatic kinetic resolution (EKR) of 2-arylpropanoic acids (‘profens’), as the active pharmaceutical ingredients (APIs) of blockbuster non-steroidal anti-inflammatory drugs (NSAIDs), by using various trialkyl orthoesters as irreversible alkoxy group donors in organic media, were performed. The enzymatic reactions of target [...] Read more.
Studies into the enzymatic kinetic resolution (EKR) of 2-arylpropanoic acids (‘profens’), as the active pharmaceutical ingredients (APIs) of blockbuster non-steroidal anti-inflammatory drugs (NSAIDs), by using various trialkyl orthoesters as irreversible alkoxy group donors in organic media, were performed. The enzymatic reactions of target substrates were optimized using several different immobilized preparations of lipase type B from the yeast Candida antarctica (CAL-B). The influence of crucial parameters, including the type of enzyme and alkoxy agent, as well as the nature of the organic co-solvent and time of the process on the conversion and enantioselectivity of the enzymatic kinetic resolution, is described. The optimal EKR procedure for the racemic profens consisted of a Novozym 435-STREM lipase preparation suspended in a mixture of 3 equiv of trimethyl or triethyl orthoacetate as alkoxy donor and toluene or n-hexane as co-solvent, depending on the employed racemic NSAIDs. The reported biocatalytic system provided optically active products with moderate-to-good enantioselectivity upon esterification lasting for 7–48 h, with most promising results in terms of enantiomeric purity of the pharmacologically active enantiomers of title APIs obtained on the analytical scale for: (S)-flurbiprofen (97% ee), (S)-ibuprofen (91% ee), (S)-ketoprofen (69% ee), and (S)-naproxen (63% ee), respectively. In turn, the employment of optimal conditions on a preparative-scale enabled us to obtain the (S)-enantiomers of: flurbiprofen in 28% yield and 97% ee, ibuprofen in 45% yield and 56% ee, (S)-ketoprofen in 23% yield and 69% ee, and naproxen in 42% yield and 57% ee, respectively. The devised method turned out to be inefficient toward racemic etodolac regardless of the lipase and alkoxy group donor used, proving that it is unsuitable for carboxylic acids possessing tertiary chiral centers. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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Review

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28 pages, 31227 KiB  
Review
Diversifying Arena of Drug Synthesis: In the Realm of Lipase Mediated Waves of Biocatalysis
by Sahil Verma, Rahul Narayanlal Choudhary, Akash Prakash Kanadje and Uttam Chand Banerjee
Catalysts 2021, 11(11), 1328; https://doi.org/10.3390/catal11111328 - 31 Oct 2021
Cited by 10 | Viewed by 2718
Abstract
Hydrolases, being most prominent enzymes used in industrial processes have left no stone unturned in fascinating the pharmaceutical industry. Lipases, being a part of acyl hydrolases are the ones that function similarly to esterases (except an interfacial action) wherein they generally catalyze the [...] Read more.
Hydrolases, being most prominent enzymes used in industrial processes have left no stone unturned in fascinating the pharmaceutical industry. Lipases, being a part of acyl hydrolases are the ones that function similarly to esterases (except an interfacial action) wherein they generally catalyze the hydrolysis of ester bonds. Be it in terms of stereoselectivity or regioselectivity, lipases have manifested their promiscuous proficiency in rendering biocatalytic drug synthesis and intermediates thereof. Industrial utilization of lipases is prevalent since decades ago, but their distinctive catalytic competencies have rendered them suitable for maneuverability in various tides of biocatalytic industrial process development. Numbers of exquisite catalysts have been fabricated out of lipases using nanobiotechnology whereby enzyme reusability and robustness have been conferred to many of the organic synthesis procedures. This marks a considerable achievement of lipases in the second wave of biocatalysis. Furthermore, in the third wave an advent of genetic engineering has fostered an era of customized lipases for suitable needs. Be it stability or an enhanced efficacy, genetic engineering techniques have ushered an avenue for biocatalytic development of drugs and drug intermediates through greener processes using lipases. Even in the forthcoming concept of co-modular catalytic systems, lipases may be the frontiers because of their astonishing capability to act along with other enzymes. The concept may render feasibility in the development of cascade reactions in organic synthesis. An upcoming wave demands fulfilling the vision of tailored lipase whilst a far-flung exploration needs to be unveiled for various research impediments in rendering lipase as a custom fit biocatalyst in pharmaceutical industry. Full article
(This article belongs to the Special Issue Applications of Hydrolases in Medicinal Chemistry)
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