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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Benzisothiazol is another sulfur-containing compound with more selectivity towards HDAC6 (Wang et al., 2017). It has a core structure of ebsulfur. Ebsulfur is a known analog of Ebselen, which is a clinically safe and a weak inhibitor of HDAC enzymes (Wang et al., 2017). Derivatives of Benzothiazole having sulfur exhibited potent anti-proliferative activity (GI50 = 2.01 μM) against SH-SY-5Y cancer cell line in a dose and time-dependent manner, which is slightly better than the reference drug SAHA (GI50 = 2.90 μM). This compound efficiently inhibits HDAC1 and HDAC6 isoforms with IC50 values in nanomolar concentrations. Furthermore, Benzothiazole inhibited colony formation capacity of SH-SY-5Y cells (Choi et al., 2019). Further studies on structure-inhibition relationships lead to the development of another compound called RBC-2008. RBC-2008 is synthesized based on the structure of RBC-2004 by adding a hydroxamic acid to the benzoyl moiety (Wang et al., 2017). RBC-2008, although inhibited all 11 HDAC enzymes, showed more selectivity towards HDAC6 (Wang et al., 2017).
Toward Clinical Pharmacologic Otoprotection
Published in Stavros Hatzopoulos, Andrea Ciorba, Mark Krumm, Advances in Audiology and Hearing Science, 2020
Colleen G. Le Prell, Kelly Roth, Kathleen C. M. Campbell
Glutathione peroxidase (GPx) speeds the reaction through which GSH neutralizes hydrogen peroxide. Ebselen is a synthetic selenium-containing compound that acts as a GPx mimic and inducer both generally [for review, see Azad and Tomar (2014)] and in the ear (Kil et al., 2007). Ebselen catalyzes GSH redox reactions more efficiently than GPx (Wendel et al., 1984) and prevents mitochondrial membrane permeability transition (MPT) pores from forming and/or opening (Tak and Park, 2009). When opened, the MPT pores allow GSH to escape the mitochondria, which decreases ROS scavenging. Ebselen is a peroxynitrite scavenger and it scavenges nitric oxide and organic hydroperoxides. Ebselen also has anti-inflammatory effects [attributed to downregulation of TNF-alpha, see Tewari et al. (2009); for recent review, see Mlochowski and Wojtowicz-Mlochowska (2015)] and inhibits the second messenger inositol monophosphate (IMPase) [see Masaki et al. (2016); Singh et al. (2016)].
Clostridium
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Emilio Aranda, María G. Córdoba, María J. Benito, Juan José Córdoba
Pirazzini et al.108 studied a Thioredoxin Reductase-thioredoxin Redox System cleaves the interchain disulfide bond of BoNTs on the cytosolic surface of synaptic rat vesicles which blocked the different BoNTs tested within a very similar concentration range, suggesting that the interchain disulfide reduction is closely similar for different BoNTs serotypes. These in vitro results were validated in vivo using digit abduction score (DAS) assay, a well-established model to compare potency and duration of BoNTs.115 All tested molecules were very effective in reducing the degree and duration of paralysis induced by the local injection of BoNT/A and BoNT/C. For the first time, it was shown that small molecules effectively prevent the paralytic activity of BoNTs. As a proof of concept, they also tested one of these inhibitors, Ebselen, a compound reported to target both TrxR and Trx,116 in the lethality assay. Ebselen, preventively administered via intraperitoneal injection, was very effective in protecting animals from a lethal amount of BoNT/A, both by prolongation of the time to death and by reduction of the number of deaths108 (Table 9.1).
Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Diego Benítez, Jaime Franco, Florencia Sardi, Alejandro Leyva, Rosario Durán, Gahee Choi, Gyongseon Yang, Taehee Kim, Namyoul Kim, Jinyeong Heo, Kideok Kim, Honggun Lee, Inhee Choi, Constantin Radu, David Shum, Joo Hwan No, Marcelo A. Comini
Ebselen was the only hit for which there was a clear correlation between anti-trypanosomal activity and on-target effect in T. brucei (intracellular oxidative milieu). This compound has been shown to inhibit trypanothione reductase by covalent formation of seleno-sulphide bonds with enzyme's cysteines60. Thus, the strong oxidant effect exerted by Ebselen against bloodstream T. brucei is likely consequence of the simultaneous inhibition of two major enzymes from the parasite thiol-redox metabolism: trypanothione reductase and TryS. Ebselen represents an interesting multi-target compound (the essential Cys327 from T. brucei hexokinase has also been shown to be irreversibly oxidised and inactivated by Ebselen)61,62 that has been explored in different clinical trials including acute ischaemic stroke63, bipolar disorders in substitution of lithium-therapy64,65 and prevention of noise-induced hearing loss66. The promiscuity of Ebselen to react with cysteine residues may hamper its clinical efficacy (i.e. sequestration by the cysteine residue from the abundant serum albumin) and repositioning. However, our findings open the possibility for designing new derivatives with improved target selectivity.
Promising treatment strategies to combat Staphylococcus aureus biofilm infections: an updated review
Published in Biofouling, 2020
P. S. Seethalakshmi, Riya Rajeev, George Seghal Kiran, Joseph Selvin
Ebselen is an antipsychotic drug which induces lithium-like effects due to the inhibition of inositol monophosphatase, making it a suitable drug for bipolar disorder (Singh et al. 2013). Thangamani, Younis, et al. (2015) reported that ebselen possessed antibacterial activity towards linezolid-resistant S. aureus, mupirocin-resistant S. aureus, MRSA, and VRSA strains. Ebselen, at a concentration of 2 µg ml−1 decreased the biomass of established S. aureus biofilms by 60%. Cytotoxic assays in human keratinocyte cells (HaCat) indicated 50% inhibition of cell proliferation. Synergistic antibacterial activity of ebselen was observed with various antibiotics such as fusidic acid, daptomycin, mupirocin, and retapamulin against S. aureus. The ELISA test performed using the supernatant of skin homogenates of mice suffering from MRSA wounds after treatment with 1% and 2% ebselen revealed decreased levels of pro-inflammatory cytokines. Later, Ngo et al. (2016) synthesized ebsulfur, a derivative of ebselen obtained by replacing selenium with sulfur and analyzed its antimicrobial, ant-ibiofilm and anti-virulence properties against S. aureus. Ebsulfur had an MIC ranging from 0.5 µg ml−1 to 7.8 µg ml−1 against the tested S. aureus strains which included methicillin resistant and sensitive strains. Ebsulfur, at a concentration of 125 µg ml−1, reduced biofilms of S. aureus by 50%.
Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks
Published in Gut Microbes, 2020
David Stewart, Farhan Anwar, Gayatri Vedantam
Ebselen is a synthetic organoselenium compound that possess anti-inflammatory and antioxidative properties.78 It has been proposed that Ebselen modifies proteins via seleno-sulfide conjugation at cysteine residues.79,80 In recent years, Ebselen has been reported to have antimicrobial functions against multiple clinically relevant microorganisms. Notably, Ebselen has been shown to have profound effects on multidrug-resistant staphylococcal infections; this small molecule inhibits toxin production, reduce bacterial load, and reduces established biofilms,78 while also acting synergistically with traditional antibiotics. Against vancomycin-resistant enterococci (VRE), Ebselen exhibited potent bactericidal activity in vitro, and a distinct lack of Ebselen-resistant VRE after prolonged passaging.81 As with multidrug-resistant staphylococcal biofilms, Ebselen was shown to significantly reduce established VRE biofilms.81 With the antimicrobial activity demonstrated against other notable pathogens, it becomes an attractive option to explore as an antimicrobial against CD. Work by Bender et al.80 and Beilhartz et al.82 identified and demonstrated the ability of Ebselen to inhibit the activity of CD toxins.