2-Hydroxybenzylamine

First-in-human study assessing safety, tolerability, and pharmacokinetics of 2-hydroxybenzylamine acetate, a selective dicarbonyl electrophile scavenger, in healthy volunteers.[Pubmed:30611293]

BMC Pharmacol Toxicol. 2019 Jan 5;20(1):1.

BACKGROUND: 2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer's disease. METHODS: In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. RESULTS: Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1-2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. CONCLUSIONS: 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03176940).

Subchronic (90-day) repeated dose oral toxicity study of 2-hydroxybenzylamine acetate in rabbit.[Pubmed:30359704]

Regul Toxicol Pharmacol. 2018 Dec;100:52-58.

2-Hydroxybenzylamine (2-HOBA), a naturally occurring compound found in buckwheat, has potential for use as a nutrition supplement due to its ability to protect against the damaging effects of oxidative stress. In a series of rodent toxicity studies, 2-HOBA acetate was well-tolerated and did not produce any toxic effects over 28 or 90 days of repeated oral administration. However, it remained necessary to test the potential toxicity of 2-HOBA acetate in a non-rodent species. In this investigation, 2-HOBA acetate was orally administered to male and female New Zealand White Rabbits for 90 days at doses of 100, 500, and 1000mg.kg BW(-1).day(-1) (n=5 per sex/group). As previously observed in rodents, 2-HOBA acetate administration was well tolerated. No toxic effects of 2-HOBA acetate were detected in body weight, feed consumption, hematology, blood chemistry, urine chemistry, organ weights, gross pathology or histopathology. Based on these findings, the no-observed-adverse-effect-level of 2-HOBA acetate in rabbits was determined to be 1000mg.kg BW(-1).day(-1), which was the highest dose tested. These results provide further support for the safety of 2-HOBA acetate administration.

Subchronic (90-day) repeated dose toxicity study of 2-hydroxybenzylamine acetate in rats.[Pubmed:30266239]

Regul Toxicol Pharmacol. 2018 Nov;99:225-232.

2-Hydroxybenzylamine (2-HOBA), a naturally occurring compound found in buckwheat, can protect cells and tissues from oxidative stress. In this study, 2-HOBA acetate was orally administered to male and female rats for 90 consecutive days at doses of 100, 500, and 1000mg.kg BW(-1).d(-1) (n=20 per sex/group). Subchronic administration of 2-HOBA was well tolerated at all dose levels. 2-HOBA-treated male rats were slightly heavier in the last weeks of the study, but this difference was very small (<5%), did not show a dose-response relationship, and was not observed in female rats. Similarly, some statistically significant changes in serum biochemistry and hematology parameters were noted, but these were not considered to be of biological or toxicological significance. Sporadic differences in organ weights were observed between groups, but all were small (<10%) and unlikely to indicate toxicity. The incidence of histopathological lesions was similar between treated and control groups across all organs. Based upon these findings, the no-observed-adverse-effect level was determined to be>/=1000mg.kg BW(-1).d(-1), which was the highest dose tested. These results further support no toxicity associated with oral consumption of 2-HOBA acetate in rats and the continued development of 2-HOBA as a dietary supplement or functional food.

In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate.[Pubmed:30253245]

Food Chem Toxicol. 2018 Nov;121:541-548.

2-Hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive gamma-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2-HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA.

Acute and 28-day repeated dose toxicity evaluations of 2-hydroxybenzylamine acetate in mice and rats.[Pubmed:30075181]

Regul Toxicol Pharmacol. 2018 Oct;98:190-198.

2-Hydroxybenzylamine (2-HOBA), a compound naturally found in buckwheat, has been shown to protect cells and tissues from the damaging effects of oxidative stress. The purpose of this report was to evaluate 2-HOBA in preclinical oral rodent toxicity studies. This report includes the results from three oral toxicity studies in rodents: a preliminary 28-day feeding study in mice, a 14-day acute oral toxicity study in rats, and a 28-day repeated dose oral toxicity study in rats. The preliminary mouse feeding study showed no adverse effects of 2-HOBA at concentrations up to 0.456% by weight in feed, but decreased food intake and weight loss were observed at 1.56% 2-HOBA in the diet, likely due to poor palatability. In the acute dosing study, 2000mg/kg BW 2-HOBA resulted in mortality in one of the six tested female rats, indicating a median lethal dose of 2500mg/kg BW. In the 28-day repeated oral dose study, small differences were observed between 2-HOBA treated and control group rats, but none of these differences were determined to be of toxicological significance. Together, these studies support the lack of toxicity of oral administration of 2-HOBA acetate at doses up to 1000mg/kg BW d(-1) in rodents.

Reactive Carbonyl Species Scavengers-Novel Therapeutic Approaches for Chronic Diseases.[Pubmed:28993795]

Curr Pharmacol Rep. 2017 Apr;3(2):51-67.

PURPOSE OF THE REVIEW: To summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease. RECENT FINDINGS: The newly developed 2-aminomethylphenol class of scavengers shows great promise in preclinical trials for a number of diverse conditions including neurodegenerative diseases and cardiovascular disease. In addition, new studies with the thiol-based and imidazole-based scavengers have found new applications outside of adjunctive therapy for chemotherapeutics. SUMMARY: Reactive oxygen species (ROS) generated by cells and tissues act as signaling molecules and as cytotoxic agents to defend against pathogens, but ROS also cause collateral damage to vital cellular components. The polyunsaturated fatty acyl chains of phospholipids in the cell membranes are particularly vulnerable to damaging peroxidation by ROS. Evidence suggests that the breakdown of these peroxidized lipids to reactive carbonyls species plays a critical role in many chronic diseases. Antioxidants that abrogate ROS-induced formation of reactive carbonyl species also abrogate normal ROS signaling and thus exert both beneficial and adverse functional effects. The use of scavengers of reactive dicarbonyl species represent an alternative therapeutic strategy to potentially mitigate the adverse effects of ROS without abrogating normal signaling by ROS. In this review, we focus on three classes of reactive carbonyl species scavengers: thiol-based scavengers (2-mercaptoethanesulfonate and amifostine), imidazole-based scavengers (carnosine and its analogs), and 2-aminomethylphenols-based scavengers (pyridoxamine, 2-Hydroxybenzylamine, and 5'-O-pentyl-pyridoxamine) that are either undergoing pre-clinical studies, advancing to clinical trials, or are already in clinical use.

Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension.[Pubmed:28680578]

Pulm Circ. 2017 Feb 1;7(1):186-199.

Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary-specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH-causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild-type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin-3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2-Hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine-driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease-modifying therapeutics that could be rapidly translated to human studies.

Molecular docking and molecular dynamics simulation analyses of urea with ammoniated and ammoxidized lignin.[Pubmed:27846422]

J Mol Graph Model. 2017 Jan;71:58-69.

Ammoniated lignin, prepared through the Mannich reaction of lignin, has more advantages as a slow-release carrier of urea molecules than ammoxidized lignin and lignin. The advantages of the ammoniated lignin include its amine groups added and its high molecular mass kept as similar as that of lignin. Three organic molecules including guaiacyl, 2-Hydroxybenzylamine and 5-carbamoylpentanoic acid are monomers respectively in lignin, ammoniated lignin and ammoxidized lignin. We studied the difference between the interactions of lignin, ammoniated lignin and ammoxidized lignin with respect to urea, based on radial distribution functions (RDFs) results from molecular dynamics (MD) simulations. Glass transition temperature (Tg) and solubility parameter (delta) of ammoniated and ammoxidized lignin have been calculated by MD simulations in the constant-temperature and constant-pressure ensemble (NPT). Molecular docking results showed the interaction sites of the urea onto the ammoniated and ammoxidized lignin and three different interaction modes were identified. Root mean square deviation (RMSD) values could indicate the mobilities of the urea molecule affected by the three different interaction modes. A series of MD simulations in the constant-temperature and constant-volume ensemble (NVT) helped us to calculate the diffusivity of urea which was affected by the content of urea in ammoniated and ammoxidized lignin.

Immune activation caused by vascular oxidation promotes fibrosis and hypertension.[Pubmed:26595812]

J Clin Invest. 2016 Jan;126(1):50-67.

Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-gamma. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-gamma, IL-17A, and TNF-alpha. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-Hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.

Polynuclear nickel(II) complexes: a magnetostructural study of Ni(II)4, Ni(II)6, and Ni(II)9 species with oxime ligands.[Pubmed:19552389]

Inorg Chem. 2009 Jul 20;48(14):6781-93.

Syntheses, crystal structures, and magnetic properties are reported for a tetrametallic (complex 1), a nonametallic (complex 2), and two hexametallic (complexes 3 and 4) nickel(II) clusters, namely, [Ni(4)(HL(1))(2)(mu-OAc)(2)(MeOH)] (1), [Ni(9)(L(2))(10)(mu(3)-OH) (2) (mu-OH) (2) (mu-OH (2))(2)(OH(2))(6)](ClO(4)) (4) (2), [Ni(6)(L(2))(9)(L(2)H)(MeOH)(H(2)O)(2)](ClO(4))(3) (3), and [Ni(6)(L(3))(3)(mu(3)-O)(2)](ClO(4))(2) (4), where H(4)L(1) represents N,N'-dimethyl-N,N'-ethylene-bis(5-bromo-3-formyloxime-2-Hydroxybenzylamine); HL(2), 1-methylimidazole-2-aldoxime; and H(2)L(3), N,N'-bis(2,3-butanedionemonoxime-2-ene)-3(aminomethyl)benzylamine. The structure of 1 can be considered as two face-sharing bioctahedral units of [Ni(2)(mu-O(phen))(2)(mu-OAc)] bridged by a two-atom (-N-O-) oximate linker. The Ni(II)...Ni(II) distances of av. 2.935 A preclude metal-metal bonding, although they are remarkably short. Variable-temperature magnetic susceptibility data are fitted to obtain the parameters J (1) = +8.0 cm(-1), J(2) = -16.0 cm (-1), and g = 2.19 (H= -2 JS(i) x S(j)). The ferromagnetic coupling J (1) operates between the nickel(II) centers in the face-sharing bioctahedral units, whereas J(2) represents the antiferromagnetic interactions mediated by a single (-N-O-) bridge separating the two nickel centers at a distance of approximately 4.71 A. A rationale for the disparate nature of interactions based on a comparison with those reported in the literature is forwarded. The structure of 2 consists of two [Ni(4)(L(2))(5)] units linked covalently to a central nickel atom by four oximate and two hydroxy oxygen atoms, resulting in a central octahedral NiO(6) core and thus yielding the nonanuclear nickel(II) cluster. The magnetic data were analyzed by a "two-J" model, yielding pairwise antiferromagnetic exchange interactions, J(1) = -24.0 cm (-1) and J(2) = -5.8 cm (-1), between the nickel centers. The spin ground state of S(t) = 1.0 has been confirmed by magnetization measurements (variable-temperature, variable-field) at different fields. The structure of 3 contains six nickel(II) centers, each of which is six-coordinated but with different coordination environments: NiN(6), NiO(6), NiN(3)O(3)(2x), NiN(4)O(2), and NiNO(5). The ground-state spin has been observed to be S(t) = 1.0 with the axial zero-field splitting parameter D = -7.2 cm(-1). Complex 4 is a rare example of dimeric [Ni(3)(mu(3)-O)](4+) units, in which each of six nickel(II) centers is in square-planar geometry with low-spin d(8) Ni(II) centers, thus rendering diamagnetism to complex 4.

Task-specific ionic liquids bearing 2-hydroxybenzylamine units: synthesis and americium-extraction studies.[Pubmed:16432910]

Chemistry. 2006 Apr 3;12(11):3074-81.

The synthesis of two task-specific ionic liquids (TSILs) bearing 2-Hydroxybenzylamine entities is described. These compounds are based on an imidazolium substructure onto which one hydrobenzylamine-complexing moiety is grafted. We have demonstrated that, whether pure or diluted, TSIL is able to extract americium ions. Furthermore, recovery of americium from the IL phase into a receiving phase can be achieved under acidic conditions. A possible mechanism for the metal-ion partitioning is presented, in which the extraction system is driven by an ion-exchange mechanism.

Spectroscopic studies of metal complexes with redox-active hydrogenated Schiff bases.[Pubmed:11300556]

Spectrochim Acta A Mol Biomol Spectrosc. 2001 Mar 1;57(3):451-60.

Synthesis and spectroscopic (IR, UV-visible, ESR) characterization of metal(II) complexes M(Lx')2, (where M = Co(II), NI(II), VO(II), Pd(II), Lx' = L1', L2', L3' are monoanion of unsubstituted, 5-Cl and 5-Br substituted-2-Hydroxybenzylamine) with redox-active N-(3,5-ditert-butyl-4-hydroxyphenyl)-2-Hydroxybenzylamine ligands as well as radical species generated from these compounds by the oxidation with PbO2 are reported. ESR studies indicate that the VO(Lx')2 and Ni(Lx')2 complexes, in opposite to their salicylaldimine precursors, are more readily oxidized with lead dioxide and results in the formation of the indophenoxyl type stable radical. The formed radical species are very similar to each other and quite different from those of the salicylaldimine analogous according to their g-factors and hyperfine coupling constants. The nine line radical spectra observed in the oxidation of Co(Lx')2, on standing under vacuum, gradually converted to the signals characteristic of the low-spin Co(II) (g(x,y) = 2.276, g(z) = 1.998, A(xy)Co = 122.7 G, A(z)Co = 150 G) and radical containing Co(III) intermediate with g(x,y) = 2.015, A(xy)Co = 4.66 G, g(z) = 1.989, A(z)Co = 10 G were also observed.

Preparation of general proteinase substrates using 3,5-dinitrosalicylaldehyde.[Pubmed:8905466]

J Biochem Biophys Methods. 1996 Oct 15;33(1):31-41.

To search for new proteinases in Bacillus subtilis we have developed a general method for synthesizing chromogenic proteinase substrates using 3,5-dinitrosalicylaldehyde (DNSA). Hammersten casein and soluble protein from extracts from B. subtilis cells were labeled with DNSA in the presence of NaBH4. After dialysis (pH 7.8), the resultant 3,5-dinitro-2-hydroxybenzyl-casein (DNHB-casein) and DNHB-bacterial cell protein solutions were a light orange color. A model compound, N-benzyl-3,5-dinitro-2-Hydroxybenzylamine was synthesized and estimated to have a molar absorption coefficient of 14,100 M-1 cm-1 at 366 nm at pH 8, which was used to calculate dye loading on casein. Chromogenic substrates prepared in this way should retain positive charges on lysine residues. DNHB-casein and DNHB-bacterial cell protein were incubated with varying concentrations of subtilisin BPN' for varying times, precipitated with trichloroacetic acid and centrifuged. The acid-soluble supernatant fractions were made basic with NaOH and absorbances were measured at 366 nm, the absorption maximum. Color production was proportional to subtilisin concentration and times of incubation; under the assay conditions used, the limit of detection of subtilisin was about 100 ng. Five proteinase activities were detected in soluble extracts of B. subtilis using DNHB-labeled proteins as substrates.