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Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory biomolecules Review Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential Igor A. Schepetkin 1, Mark B. Plotnikov 2 , Andrei I. Khlebnikov 3,4 , Tatiana M. Plotnikova 5 and Mark T. Quinn 1,* 1 Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA; [email protected] 2 Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, 634028 Tomsk, Russia; [email protected] 3 Kizhner Research Center, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia; [email protected] 4 Scientific Research Institute of Biological Medicine, Altai State University, 656049 Barnaul, Russia 5 Department of Pharmacology, Siberian State Medical University, 634050 Tomsk, Russia; [email protected] * Correspondence: [email protected]; Tel.: +1-406-994-4707; Fax: +1-406-994-4303 Abstract: Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti- stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin- dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and Citation: Schepetkin, I.A.; Plotnikov, non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, M.B.; Khlebnikov, A.I.; Plotnikova, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and T.M.; Quinn, M.T. Oximes: Novel one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This Therapeutics with Anticancer and feature, together with the high polarity of oxime groups, may lead to a significantly different mode of Anti-Inflammatory Potential. interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small Biomolecules 2021, 11, 777. https:// doi.org/10.3390/biom11060777 changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Academic Editor: Loredana Salerno Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed. Received: 9 April 2021 Keywords: oxime; kinase inhibitor; indirubin; nitric oxide; molecular modeling; inflammation; cancer Accepted: 19 May 2021 Published: 22 May 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Oxime compounds have been investigated for decades because of their significant published maps and institutional affil- roles as acetylcholinesterase reactivators and their use as therapeutics for a number of iations. diseases [1–3]. Metabolites of various oximes have also been identified in plants as in- termediates in biosynthesis and can facilitate a range of processes important for plant growth and development (for review [4]). Since amidoximes were found to be synthetic antimicrobial agents [5], oximes with different scaffolds have been developed for the Copyright: © 2021 by the authors. treatment of bacterial infections, including tuberculosis [6–10]. Oximes have also been Licensee MDPI, Basel, Switzerland. reported to exhibit a wide range of biological activities, such as anti-inflammatory [11–15] This article is an open access article and anti-human immunodeficiency (HIV) agents that can inhibit HIV protease [16,17]. distributed under the terms and Indeed, the anti-inflammatory activity of some oximes has been reported to be comparable conditions of the Creative Commons to standard anti-inflammatory drugs, such as indomethacin, diclofenac, and dexametha- Attribution (CC BY) license (https:// sone [18–20]. On the other hand, the introduction of an oxime group into an appropriate creativecommons.org/licenses/by/ chemical backbone is a reasonable approach for the preparation of cytotoxic agents, and 4.0/). Biomolecules 2021, 11, 777. https://doi.org/10.3390/biom11060777 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 33 Biomolecules 2021, 11, 777 2 of 33 20]. On the other hand, the introduction of an oxime group into an appropriate chemical backbone is a reasonable approach for the preparation of cytotoxic agents, and many ox- ime derivatives have been reported to have therapeutic activity for cancer [2,21–27] and many oxime derivatives have been reported to have therapeutic activity for cancer [2,21–27] neurodegenerative disorders [28–30]. and neurodegenerative disorders [28–30]. The introduction of oxime groups has been reported to increase the biological activity The introduction of oxime groups has been reported to increase the biological activity of several natural compounds (Figure 1). For example, oxime derivatives of gossypol, a of several natural compounds (Figure1). For example, oxime derivatives of gossypol, a natural phenol derived from the cotton plant, exhibit antiviral, insecticidal, and fungicidal natural phenol derived from the cotton plant, exhibit antiviral, insecticidal, and fungicidal activity [31]. Another example is psammaplin A analog, the free oxime group which was activity [31]. Another example is psammaplin A analog, the free oxime group which was responsible for high anticancer activity [32]. Moreover, oxime derivatives of radicicol, a responsible for high anticancer activity [32]. Moreover, oxime derivatives of radicicol, a macrocyclicmacrocyclic antifungalantifungal antibiotic,antibiotic, showedshowed higherhigher inhibitoryinhibitory activityactivity towardtoward SrcSrc tyrosinetyrosine kinasekinase andand anticanceranticancer activityactivity inin comparisoncomparison withwith thethe parentparent compoundcompound [[33,34].33,34]. Similarly, thethe oximeoxime modificationsmodifications mademade onon thethe biflorinbiflorin structurestructure ledled toto anan increase increase in in antibacterial antibacterial potentialpotential [[7].7]. AcylatedAcylated oximesoximes derivedderived fromfrom triterpenestriterpenes havehave shownshown cytotoxiccytotoxic oror antipro-antipro- liferativeliferative activityactivity againstagainst manymany lineslines ofof cancercancer cells cells [ 35[35].]. TheThe biologicalbiological activityactivityof of several several indirubinindirubin oxime oxime derivatives derivatives is muchis much higher higher than than that ofthat the of plant the alkaloidplant alkaloid indirubin indirubin [36,37]. Finally,[36,37]. weFinally, recently we reported recentlythat reported the oxime that derivativethe oxime of derivative the natural of alkaloid the natural tryptanthrin alkaloid istryptanthrin a c-Jun N-terminal is a c-Jun kinase N-terminal (JNK) inhibitorkinase (JNK) [38] (Figureinhibitor1). [38] (Figure 1). FigureFigure 1.1. IntroductionIntroduction ofof oximeoxime groupsgroups increasesincreases kinase kinase inhibitory inhibitory activity activity of of natural natural compounds. compounds. Oximes have been used in the design of various kinase inhibitors, including phos- Oximes have been used in the design of various kinase inhibitors, including phos- phatidyl inositol 3-kinase (PI3K) inhibitors [39], phosphorylase kinase (PhK) [40], and phatidyl inositol 3-kinase (PI3K) inhibitors [39], phosphorylase kinase (PhK) [40], and JNK JNK [38,41] (see Tables1 and2). For example, indirubin oximes are of interest because of [38,41] (see Tables 1 and 2). For example, indirubin oximes are of interest because of their their high affinity binding to the ATP-binding site of protein kinases involved in tumorige- high affinity binding to the ATP-binding site of protein kinases involved in tumorigenesis, nesis, e.g., cyclin-dependent kinases (CDK), glycogen synthase kinase (GSK) 3β, vascular e.g., cyclin-dependent kinases (CDK), glycogen synthase kinase (GSK) 3β, vascular endo- endothelial growth factor receptor 2 (VEGFR-2), c-Src, and casein kinase 2 (CK2) [42–48]. thelial growth factor receptor 2 (VEGFR-2), c-Src, and casein kinase 2 (CK2) [42–48]. Many Many of these kinases are molecular targets for compounds with anticancer activity. of these kinases are molecular targets for compounds with anticancer activity. Biomolecules 2021BiomoleculesBiomolecules, 11, x 2021 2021, 11,, ,11 x ,, xx 3 of 33 3 of3 of33 33 Biomolecules 2021, 11, 777 3 of 33 Table 1. IndirubinTableTable oxime-based1. 1.Indirubin Indirubin oxime-based kinase oxime-based inhibi kinasetors kinase and inhibi theirinhibitors kinasetors and and targets.their their kinase kinase targets. targets. Table 1. Indirubin oxime-based kinase inhibitors and their kinase targets. Compound CompoundCompoundR5 R5 R56 R7 R6R 6 R7R 7 R3′ R3R′ 3′ R5′ R6′ R5R′ 5′ R6R′ 6′ CompoundCompound R5 R5R 6 R6 R7 R7 RR330′′ R5′′ R50 R6′′ R60 1 1 1 H H H H H H H H=N-OH =N-OH=N-OH H H H H H H 1 1 HH HH HH =N-OH H HH H 2 H H H =N-OAc H H 22 2 H H HH H HH=N-OAc =N-OAc H H H HH H 3 3 3 H H H H H H=N-OCH H H 2CHOHCH=N-OCH=N-OCH2OH2CHOHCH2CHOHCH H2OH 2OH H H H H H 3 3 HH HH HH =N-OCH=N-OCH22CHOHCH2OHOH H HH H 3 2 44 4 OCH4 3 OCHOCHH H3 H H H =N-O-CHOH-CH
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