Table of Contents

    Topic review


    View times: 6
    Submitted by: Mark Quinn


    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 non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide.

    1. Introduction

    Oxime compounds have been investigated for decades because of their significant roles as acetylcholinesterase reactivators and their use as therapeutics for a number of diseases [1][2][3]. Metabolites of various oximes have also been identified in plants as intermediates 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 treatment of bacterial infections, including tuberculosis [6][7][8][9][10]. Oximes have also been reported to exhibit a wide range of biological activities, such as anti-inflammatory [11][12][13][14][15] and anti-human immunodeficiency (HIV) agents that can inhibit HIV protease [16][17]. Indeed, the anti-inflammatory activity of some oximes has been reported to be comparable to standard anti-inflammatory drugs, such as indomethacin, diclofenac, and dexamethasone [18][19][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 oxime derivatives have been reported to have therapeutic activity for cancer [2][21][22][23][24][25][26][27] and neurodegenerative disorders [28][29][30].
    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 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 responsible for high anticancer activity [32]. Moreover, oxime derivatives of radicicol, a macrocyclic antifungal antibiotic, showed higher inhibitory activity toward Src tyrosine kinase and anticancer activity in comparison with the parent compound [33][34]. Similarly, the oxime modifications made on the biflorin structure led to an increase in antibacterial potential [7]. Acylated oximes derived from triterpenes have shown cytotoxic or antiproliferative activity against many lines of cancer cells [35]. The biological activity of several indirubin oxime derivatives is much higher than that of the plant alkaloid indirubin [36][37]. Finally, we recently reported that the oxime derivative of the natural alkaloid tryptanthrin is a c-Jun N-terminal kinase (JNK) inhibitor [38] (Figure 1).
    Figure 1. Introduction of oxime groups increases kinase inhibitory activity of natural compounds.
    Oximes have been used in the design of various kinase inhibitors, including phosphatidyl inositol 3-kinase (PI3K) inhibitors [39], phosphorylase kinase (PhK) [40], and JNK [38][41]. For example, indirubin oximes are of interest because of their high affinity binding to the ATP-binding site of protein kinases involved in tumorigenesis, e.g., cyclin-dependent kinases (CDK), glycogen synthase kinase (GSK) 3β, vascular endothelial growth factor receptor 2 (VEGFR-2), c-Src, and casein kinase 2 (CK2) [42][43][44][45][46][47][48]. Many of these kinases are molecular targets for compounds with anticancer activity.

    2. Oximes with Non-kinase Targets

    While most of the identified oxime targets have been various kinases, there are some oximes that also have non-kinase targets of action. These targets include 5-lipoxygenase (5-LO), proteases, phosphodiesterase, chemokine receptors, growth factor receptors, and various channels (Table 1). For example, several indirubin oximes, such as compounds 1 and 11, have been reported to inhibit 5-LO [49], which is required for leukotriene synthesis. Replacement of the 3′-oxime in 1 by a keto group, 3′-methoxime or acetoxime resulted in loss of 5-LO inhibitory activity, indicating that a free oxime moiety in the 3′-position and a hydrogen in position N1 are required for effective inhibitory activity [49]. Additionally, newer derivatives of oleanolic acid oxime, and particularly their conjugates with acetylsalicylic acid, have been shown to downregulate the expression of cyclooxygenase 2 (COX-2) in human hepatoma HepG2 cells by modulating NF-κB signaling [50]. A reduction in COX-2 leads to reduced prostaglandin synthesis, which also inhibits inflammation in a similar fashion to other nonsteroidal anti-inflammatory drugs (NSAIDs).
    Table 1. Chemical structures of oximes with non-kinase targets and mechanisms of action.
    Compound Molecular Target/Mechanism Ref.
    32 Dual inhibitor of HNE and Pr3 [15]
    33 CCR5 antagonist [51][52]
    34 GluR6 antagonist, amelioration of inflammatory hyperalgesia [53][54]
    35 TRPA1 and TRPV1 antagonist [14]
    36 TRPA1 antagonist [55][56]
    37 TRPA1 antagonist [55][56]
    38 ASIC blocker, attenuation of pathophysiological nociceptive behaviors in CFA-inflamed and CCI rats [57]
    39 Binds directly to two components of the mitochondrial permeability pore, the VDAC, and translocator protein; inhibits MPTP opening [58]
    40 Binds to Hsp90 and provides a significant decrease in HIF-1α expression [59]

    3. Conclusions and Perspectives

    Oxime groups have been successfully introduced into a large number of therapeutic leads for the development of kinase inhibitors with anticancer and anti-inflammatory activities. The kinase selectivity of oximes does not appear to be due to the oxime group. Rather, selectivity seems to be due to the scaffold of the molecule, since some oximes are highly selective (e.g., JNK inhibitors 30 and 31 [38][41]), while others, such as indirubin, have a wide spectrum of kinase targets. In this regard, compounds 30 and 31 are of particular interest as candidates for the development of new anti-inflammatory drugs, since they are highly selective for JNKs.
    While the presence of a terminal oxime group is necessary for the activity of these compounds, the oxime group also offers a significant advantage in drug design versus carbonyl groups because of the presence of two H-bond acceptors (N and O atoms) and one donor (OH group). Additionally, the metabolism of oximes can lead to the release of NO, which may also be therapeutically beneficial [60]. The important role of the oxime group is supported by docking results revealing direct participation of oxime moiety in interactions with kinase binding sites. On the other hand, there has been some concern regarding the development of new drugs based on oxime derivatives. For example, a disadvantage of compound 11 and other indirubin derivatives is the high affinity of indirubin for ATP-binding pockets and the high degree of similarity between ATP cavities within the serine/threonine and tyrosine kinases, leading to multi-targeting. However, single molecules targeting two (or three) kinases is considered less problematic for current pharmaceutical development, and 11 is considered to have significant potential as a therapeutic for treatment of inflammatory and degenerative diseases. One major unsolved issue related to oxime derivatives is their unfavorable physicochemical properties, including poor solubility and membrane permeability, which results in low plasma bioavailability and a short half-life that limits their suitability as drugs [61][62]. However, compounds 1 and 30 can apparently cross the BBB easily, suggesting that these oximes might be useful for treating brain disorders. New approaches are being developed to improve oxime PK/PD parameters [63][64][65]. For example, complexing oxime molecules into a dendrimer carrier has been proposed as a strategy to extend their plasma duration through a mechanism of release kinetics, so that loaded drug molecules are released over a longer half-life. Choi et al. [65] demonstrated that drug-dendrimer complexes form in a specific manner, wherein each oxime molecule interacts through electrostatic attraction with the primary amine terminated at the peripheral branch of the dendrimer [65]. The importance of the oxime group in kinase binding suggests that additional introduction of this group in the structures of known kinase inhibitors could improve their potency. In addition, oximes with non-kinase targets could be screening toward a broad kinase panel for identification of novel kinase inhibitors.
    It is important to note that most of the oximes reviewed here were discovered during compound optimization and not high-throughput screening (HTS). In addition, most of these compounds were characterized in cell-free enzymatic systems and supported in independent test systems. Although compound 30 was originally discovered using HTS in a cell-based assay, the target of this compound was verified using multiple enzymatic assays, cell-based assays, structure–activity relationship (SAR) analysis, and animal experiments. Based on this compound and the absolute requirement for the oxime group in JNK inhibitory activity, we also developed compound 31, which was also validated in cell- and enzyme-based assays and in animal experiments. Thus, it is unlikely that these compounds or the oximes reviewed here are pan assay interference compounds (PAINS) [66][67]. Nevertheless, this is an important consideration in small molecule screening and will need to be addressed as oximes are developed for new therapeutics.

    The entry is from 10.3390/biom11060777


    1. Musilek, K.; Dolezal, M.; Gunn-Moore, F.; Kuca, K. Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides. Med. Res. Rev. 2011, 31, 548–575.
    2. Canario, C.; Silvestre, S.; Falcao, A.; Alves, G. Steroidal oximes: Useful compounds with antitumor activities. Curr. Med. Chem. 2018, 25, 660–686.
    3. Franjesevic, A.J.; Sillart, S.B.; Beck, J.M.; Vyas, S.; Callam, C.S.; Hadad, C.M. Resurrection and reactivation of acetylcholinesterase and butyrylcholinesterase. Chemistry 2019, 25, 5337–5371.
    4. Sorensen, M.; Neilson, E.H.J.; Moller, B.L. Oximes: Unrecognized chameleons in general and specialized plant metabolism. Mol. Plant 2018, 11, 95–117.
    5. Fuller, A.T. Antibacterial action of some aromatic amines, amidines, amidoximes, guanidines and diguanides. Biochem. J. 1947, 41, 403–408.
    6. Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E.; Varella, E.A.; Nicolaides, D.N. Recent developments in the chemistry and in the biological applications of amidoximes. Curr. Pharm. Des. 2008, 14, 1001–1047.
    7. Souza, L.G.D.; Almeida, M.C.S.; Lemos, T.L.G.; Ribeiro, P.R.V.; de Brito, E.S.; Silva, V.L.M.; Silva, A.M.S.; Braz, R.; Costa, J.G.M.; Rodrigues, F.F.G.; et al. Synthesis, antibacterial and cytotoxic activities of new biflorin-based hydrazones and oximes. Bioorg. Med. Chem. Lett. 2016, 26, 435–439.
    8. Reddy, D.S.; Kongot, M.; Netalkar, S.P.; Kurjogi, M.M.; Kumar, R.; Avecilla, F.; Kumar, A. Synthesis and evaluation of novel coumarin-oxime ethers as potential anti-tubercular agents: Their DNA cleavage ability and BSA interaction study. Eur. J. Med. Chem. 2018, 150, 864–875.
    9. Hall, J.E.; Kerrigan, J.E.; Ramachandran, K.; Bender, B.C.; Stanko, J.P.; Jones, S.K.; Patrick, D.A.; Tidwell, R.R. Anti-pneumocystis activities of aromatic diamidoxime prodrugs. Antimicrob. Agents Chemother. 1998, 42, 666–674.
    10. Clement, B.; Burenheide, A.; Rieckert, W.; Schwarz, J. Diacetyldiamidoximeester of pentamidine, a prodrug for treatment of protozoal diseases: Synthesis, in vitro and in vivo biotransformation. ChemMedChem 2006, 1, 1260–1267.
    11. Li, Q.; Zhang, J.P.; Chen, L.Z.; Wang, J.Q.; Zhou, H.P.; Tang, W.J.; Xue, W.; Liu, X.H. New pentadienone oxime ester derivatives: Synthesis and anti-inflammatory activity. J. Enzym. Inhib. Med. Chem. 2017, 33, 130–138.
    12. Liu, C.; Tang, X.; Zhang, W.; Li, G.; Chen, Y.; Guo, A.; Hu, C. 6-bromoindirubin-3′-oxime suppresses LPS-induced inflammation via inhibition of the TLR4/NF-κB and TLR4/MAPK signaling pathways. Inflammation 2019, 42, 2192–2204.
    13. Kwon, Y.J.; Yoon, C.H.; Lee, S.W.; Park, Y.B.; Lee, S.K.; Park, M.C. Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis. Jt. Bone Spine 2014, 81, 240–246.
    14. Payrits, M.; Saghy, E.; Matyus, P.; Czompa, A.; Ludmerczki, R.; Deme, R.; Sandor, Z.; Helyes, Z.; Szoke, E. A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and V1) receptor antagonist. Neuroscience 2016, 324, 151–162.
    15. Hwang, T.L.; Wang, W.H.; Wang, T.Y.; Yu, H.P.; Hsieh, P.W. Synthesis and pharmacological characterization of 2-aminobenzaldehyde oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3. Bioorg. Med. Chem. 2015, 23, 1123–1134.
    16. Komai, T.; Yagi, R.; Suzuki-Sunagawa, H.; Ishikawa, Y.; Kasuya, A.; Miyamoto, S.; Handa, H.; Nishigaki, T. Inhibition of HIV-1 protease by oxim derivatives. Biochem. Biophys. Res. Commun. 1997, 230, 557–561.
    17. Heredia, A.; Davis, C.; Bamba, D.; Le, N.; Gwarzo, M.Y.; Sadowska, M.; Gallo, R.C.; Redfield, R.R. Indirubin-3 ‘-monoxime, a derivative of a chinese antileukemia medicine, inhibits P-TEFb function and HIV-1 replication. AIDS 2005, 19, 2087–2095.
    18. Chaubal, R.; Mujumdar, A.M.; Misar, A.; Deshpande, V.H.; Deshpande, N.R. Structure-activity relationship study of androstene steroids with respect to local anti-inflammatory activity. Arzneimittelforschung 2006, 56, 394–398.
    19. Antoniadou-Vyza, E.; Avramidis, N.; Kourounakis, A.; Hadjipetrou, L. Anti-inflammatory properties of new adamantane derivatives. Design, synthesis, and biological evaluation. Arch. Pharm. 1998, 331, 72–78.
    20. Zeferino-Diaz, R.; Olivera-Castillo, L.; Davalos, A.; Grant, G.; Kantun-Moreno, N.; Rodriguez-Canul, R.; Bernes, S.; Sandoval-Ramirez, J.; Fernandez-Herrera, M.A. 22-oxocholestane oximes as potential anti-inflammatory drug candidates. Eur. J. Med. Chem. 2019, 168, 78–86.
    21. Shen, S.; Xu, N.; Klamer, G.; Ko, K.H.; Khoo, M.; Ma, D.; Moore, J.; O’Brien, T.A.; Dolnikov, A. Small-molecule inhibitor of glycogen synthase kinase 3β 6-bromoindirubin-3-oxime inhibits hematopoietic regeneration in stem cell recipient mice. Stem. Cells Dev. 2015, 24, 724–736.
    22. Zhang, X.; Castanotto, D.; Nam, S.; Horne, D.; Stein, C. 6bio enhances oligonucleotide activity in cells: A potential combinatorial anti-androgen receptor therapy in prostate cancer cells. Mol. Ther. 2017, 25, 79–91.
    23. Qu, H.E.; Huang, R.Z.; Yao, G.Y.; Li, J.L.; Ye, M.Y.; Wang, H.S.; Liu, L. Synthesis and pharmacological evaluation of novel bisindole derivatives bearing oximes moiety: Identification of novel proapoptotic agents. Eur. J. Med. Chem. 2015, 95, 400–415.
    24. Chiou, C.T.; Lee, W.C.; Liao, J.H.; Cheng, J.J.; Lin, L.C.; Chen, C.Y.; Song, J.S.; Wu, M.H.; Shia, K.S.; Li, W.T. Synthesis and evaluation of 3-ylideneoxindole acetamides as potent anticancer agents. Eur. J. Med. Chem. 2015, 98, 1–12.
    25. Blazevic, T.; Heiss, E.H.; Atanasov, A.G.; Breuss, J.M.; Dirsch, V.M.; Uhrin, P. Indirubin and indirubin derivatives for counteracting proliferative diseases. Evid. Based Complement. Alternat. Med. 2015, 2015, 654098.
    26. Xiong, B.; Chen, S.; Zhu, P.; Huang, M.; Gao, W.; Zhu, R.; Qian, J.; Peng, Y.; Zhang, Y.; Dai, H.; et al. Design, synthesis, and biological evaluation of novel thiazolyl substituted bis-pyrazole oxime derivatives with potent antitumor activities by selectively inducing apoptosis and ROS in cancer cells. Med. Chem. 2019, 15, 743–754.
    27. Galmozzi, E.; Facchetti, F.; La Porta, C.A. Cancer stem cells and therapeutic perspectives. Curr. Med. Chem. 2006, 13, 603–607.
    28. Avrahami, L.; Farfara, D.; Shaham-Kol, M.; Vassar, R.; Frenkel, D.; Eldar-Finkelman, H. Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the alzheimer disease mouse model: In vivo and in vitro studies. J. Biol. Chem. 2013, 288, 1295–1306.
    29. Sathiya Priya, C.; Vidhya, R.; Kalpana, K.; Anuradha, C.V. Indirubin-3′-monoxime prevents aberrant activation of gsk-3beta/nf-kappab and alleviates high fat-high fructose induced abeta-aggregation, gliosis and apoptosis in mice brain. Int. Immunopharmacol. 2019, 70, 396–407.
    30. Yuskaitis, C.J.; Jope, R.S. Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell. Signal. 2009, 21, 264–273.
    31. Li, L.; Li, Z.; Wang, K.L.; Liu, Y.X.; Li, Y.Q.; Wang, Q.M. Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety. Bioorg. Med. Chem. 2016, 24, 474–483.
    32. Hong, S.; Shin, Y.; Jung, M.; Ha, M.W.; Park, Y.; Lee, Y.J.; Shin, J.; Oh, K.B.; Lee, S.K.; Park, H.G. Efficient synthesis and biological activity of psammaplin a and its analogues as antitumor agents. Eur. J. Med. Chem. 2015, 96, 218–230.
    33. Soga, S.; Neckers, L.M.; Schulte, T.W.; Shiotsu, Y.; Akasaka, K.; Narumi, H.; Agatsuma, T.; Ikuina, Y.; Murakata, C.; Tamaoki, T.; et al. KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res. 1999, 59, 2931–2938.
    34. Ikuina, Y.; Amishiro, N.; Miyata, M.; Narumi, H.; Ogawa, H.; Akiyama, T.; Shiotsu, Y.; Akinaga, S.; Murakata, C. Synthesis and antitumor activity of novel O-carbamoylmethyloxime derivatives of radicicol. J. Med. Chem. 2003, 46, 2534–2541.
    35. Bednarczyk-Cwynar, B.; Zaprutko, L. Recent advances in synthesis and biological activity of triterpenic acylated oximes. Phytochem. Rev. 2015, 14, 203–231.
    36. Vougogiannopoulou, K.; Skaltsounis, A.L. From tyrian purple to kinase modulators: Naturally halogenated indirubins and synthetic analogues. Planta Med. 2012, 78, 1515–1528.
    37. Leclerc, S.; Garnier, M.; Hoessel, R.; Marko, D.; Bibb, J.A.; Snyder, G.L.; Greengard, P.; Biernat, J.; Wu, Y.Z.; Mandelkow, E.M.; et al. Indirubins inhibit glycogen synthase kinase-3β and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in alzheimer’s disease—A property common to most cycline-dependent kinase inhibitors? J. Biol. Chem. 2001, 276, 251–260.
    38. Schepetkin, I.A.; Khlebnikov, A.I.; Potapov, A.S.; Kovrizhina, A.R.; Matveevskaya, V.V.; Belyanin, M.L.; Atochin, D.N.; Zanoza, S.O.; Gaidarzhy, N.M.; Lyakhov, S.A.; et al. Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors. Eur. J. Med. Chem. 2019, 161, 179–191.
    39. Lu, L.; Sha, S.; Wang, K.; Zhang, Y.H.; Liu, Y.D.; Ju, G.D.; Wang, B.; Zhu, H.L. Discovery of chromeno[4,3-c]pyrazol-4(2H)-one containing carbonyl or oxime derivatives as potential, selective inhibitors PI3Kα. Chem. Pharm. Bull. 2016, 64, 1576–1581.
    40. Begum, J.; Skamnaki, V.T.; Moffatt, C.; Bischler, N.; Sarrou, J.; Skaltsounis, A.L.; Leonidas, D.D.; Oikonomakos, N.G.; Hayes, J.M. An evaluation of indirubin analogues as phosphorylase kinase inhibitors. J. Mol. Graph. Model. 2015, 61, 231–242.
    41. Schepetkin, I.A.; Kirpotina, L.N.; Khlebnikov, A.I.; Hanks, T.S.; Kochetkova, I.; Pascual, D.W.; Jutila, M.A.; Quinn, M.T. Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors. Mol. Pharmacol. 2012, 81, 832–845.
    42. Nam, S.; Scuto, A.; Yang, F.; Chen, W.; Park, S.; Yoo, H.S.; Konig, H.; Bhatia, R.; Cheng, X.; Merz, K.H.; et al. Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of STAT5 signaling. Mol. Oncol. 2012, 6, 276–283.
    43. Hoessel, R.; Leclerc, S.; Endicott, J.A.; Nobel, M.E.; Lawrie, A.; Tunnah, P.; Leost, M.; Damiens, E.; Marie, D.; Marko, D.; et al. Indirubin, the active constituent of a chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat. Cell Biol. 1999, 1, 60–67.
    44. Meijer, L.; Skaltsounis, A.L.; Magiatis, P.; Polychronopoulos, P.; Knockaert, M.; Leost, M.; Ryan, X.P.; Vonica, C.A.; Brivanlou, A.; Dajani, R.; et al. GSK-3-selective inhibitors derived from tyrian purple indirubins. Chem. Biol. 2003, 10, 1255–1266.
    45. Chan, Y.K.; Kwok, H.H.; Chan, L.S.; Leung, K.S.; Shi, J.; Mak, N.K.; Wong, R.N.; Yue, P.Y. An indirubin derivative, E804, exhibits potent angiosuppressive activity. Biochem. Pharmacol. 2012, 83, 598–607.
    46. Nam, S.; Buettner, R.; Turkson, J.; Kim, D.; Cheng, J.Q.; Muehlbeyer, S.; Hippe, F.; Vatter, S.; Merz, K.H.; Eisenbrand, G.; et al. Indirubin derivatives inhibit STAT3 signaling and induce apoptosis in human cancer cells. Proc. Natl. Acad. Sci. USA 2005, 102, 5998–6003.
    47. Nam, S.; Wen, W.; Schroeder, A.; Herrmann, A.; Yu, H.; Cheng, X.; Merz, K.H.; Eisenbrand, G.; Li, H.; Yuan, Y.C.; et al. Dual inhibition of janus and src family kinases by novel indirubin derivative blocks constitutively-activated STAT3 signaling associated with apoptosis of human pancreatic cancer cells. Mol. Oncol. 2013, 7, 369–378.
    48. Cheng, X.; Merz, K.H.; Vatter, S.; Christ, J.; Wolfl, S.; Eisenbrand, G. 7,7′-diazaindirubin--a small molecule inhibitor of casein kinase 2 in vitro and in cells. Bioorg. Med. Chem. 2014, 22, 247–255.
    49. Pergola, C.; Gaboriaud-Kolar, N.; Jestadt, N.; Konig, S.; Kritsanida, M.; Schaible, A.M.; Li, H.K.; Garscha, U.; Weinigel, C.; Barz, D.; et al. Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase. J. Med. Chem. 2014, 57, 3715–3723.
    50. Krajka-Kuzniak, V.; Bednarczyk-Cwynar, B.; Paluszczak, J.; Szaefer, H.; Narozna, M.; Zaprutko, L.; Baer-Dubowska, W. Oleanolic acid oxime derivatives and their conjugates with aspirin modulate the NF-κB-mediated transcription in HEPG2 hepatoma cells. Bioorg. Chem. 2019, 93, 103326.
    51. Strizki, J.M.; Xu, S.; Wagner, N.E.; Wojcik, L.; Liu, J.; Hou, Y.; Endres, M.; Palani, A.; Shapiro, S.; Clader, J.W.; et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2001, 98, 12718–12723.
    52. Tsamis, F.; Gavrilov, S.; Kajumo, F.; Seibert, C.; Kuhmann, S.; Ketas, T.; Trkola, A.; Palani, A.; Clader, J.W.; Tagat, J.R.; et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J. Virol. 2003, 77, 5201–5208.
    53. Johansen, T.H.; Drejer, J.; Watjen, F.; Nielsen, E.O. A novel non-NMDA receptor antagonist shows selective displacement of low-affinity [H-3] kainate binding. Eur. J. Pharm. Molec. Pharmacol. 1993, 246, 195–204.
    54. Guo, W.; Zou, S.P.; Tal, M.; Ren, K. Activation of spinal kainate receptors after inflammation: Behavioral hyperalgesia and subunit gene expression. Eur. J. Pharmacol. 2002, 452, 309–318.
    55. Petrus, M.; Peier, A.M.; Bandell, M.; Hwang, S.W.; Huynh, T.; Olney, N.; Jegla, T.; Patapoutian, A. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain 2007, 3, 40.
    56. McGaraughty, S.; Chu, K.L.; Perner, R.J.; Didomenico, S.; Kort, M.E.; Kym, P.R. TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol. Pain 2010, 6, 14.
    57. Munro, G.; Christensen, J.K.; Erichsen, H.K.; Dyhring, T.; Demnitz, J.; Dam, E.; Ahring, P.K. NS383 selectively inhibits acid-sensing ion channels containing 1a and 3 subunits to reverse inflammatory and neuropathic hyperalgesia in rats. CNS Neurosci. Ther. 2016, 22, 135–145.
    58. Bordet, T.; Buisson, B.; Michaud, M.; Drouot, C.; Galea, P.; Delaage, P.; Akentieva, N.P.; Evers, A.S.; Covey, D.F.; Ostuni, M.A.; et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J. Pharmacol. Exp. Ther. 2007, 322, 709–720.
    59. Kurebayashi, J.; Otsuki, T.; Kurosumi, M.; Soga, S.; Akinaga, S.; Sonoo, H. A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts. Jpn. J. Cancer Res. 2001, 92, 1342–1351.
    60. Lee, H.J.; Lee, J.; Jeong, P.; Choi, J.; Baek, J.; Ahn, S.J.; Moon, Y.; Heo, J.D.; Choi, Y.H.; Chin, Y.W.; et al. Discovery of a FLT3 inhibitor LDD1937 as an anti-leukemic agent for acute myeloid leukemia. Oncotarget 2018, 9, 924–936.
    61. Gaboriaud-Kolar, N.; Vougogiannopoulou, K.; Skaltsounis, A.L. Indirubin derivatives: A patent review (2010-present). Expert Opin. Ther. Pat. 2015, 25, 583–593.
    62. Tchoumtchoua, J.; Halabalaki, M.; Gikas, E.; Tsarbopoulos, A.; Fotaki, N.; Liu, L.; Nam, S.; Jove, R.; Skaltsounis, L.A. Preliminary pharmacokinetic study of the anticancer 6BIO in mice using an UHPLC-MS/MS approach. J. Pharm. Biomed. Anal. 2019, 164, 317–325.
    63. Lorke, D.E.; Kalasz, H.; Petroianu, G.A.; Tekes, K. Entry of oximes into the brain: A review. Curr. Med. Chem. 2008, 15, 743–753.
    64. Kobrlova, T.; Korabecny, J.; Soukup, O. Current approaches to enhancing oxime reactivator delivery into the brain. Toxicology 2019, 423, 75–83.
    65. Choi, S.K.; Thomas, T.P.; Leroueil, P.; Kotlyar, A.; Van Der Spek, A.F.; Baker, J.R., Jr. Specific and cooperative interactions between oximes and pamam dendrimers as demonstrated by 1H NMR study. J. Phys. Chem. B 2012, 116, 10387–10397.
    66. Baell, J.B. Screening-based translation of public research encounters painful problems. ACS Med. Chem. Lett. 2015, 6, 229–234.
    67. Dahlin, J.L.; Walters, M.A. How to triage PAINS-full research. Assay Drug Dev. Technol. 2016, 14, 168–174.
    1. Please check and comment entries here.