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Dilithiation of 3-amino-4-picoline (1) was achieved with sec-BuLi at room temperature. Condensation of the resulting dianion (2) with carboxylic esters afforded a wide range of 2-substituted 6-azaindoles in good yields.
Chromium picolinate, [Cr(pic)(3)], is the second most popular nutritional supplement after calcium supplements. However, the supplement, unlike simple inorganic Cr(III) salts, has been shown in the presence of biological reducing agents in vitro to catalytically generate appreciable quantities of hydroxyl radicals, resulting in DNA damage. The complex has also been shown to be remarkably stable in vitro at neutral, basic, or weakly acidic pHs. Thus, the significance of this ability to generate hydroxyl radicals depends on whether the complex is absorbed by cells intact along with the stability and concentration of the complex in cells. Consequently, male Sprague Dawley rats have been injected with (51)Cr- and (3)H-labeled [Cr(pic)(3)]. The tissue distribution, urinary and fecal loss, and subcellular hepatocyte distribution and concentration of the labels suggest that [Cr(pic)(3)] has a lifetime of less than 1 day in vivo, minimizing the potential threat from the supplement itself.
Chromium(III) tris(picolinate) [Cr(pic)3] is currently a very popular nutritional supplement; however, its safety has recently been questioned, especially with regard to its ability to act as a clastogen. At physiologically relevant concentrations, Cr(pic)3 is reduced by biological reductants, including ascorbate and thiols, to Cr(II)-containing species. These species are susceptible to air oxidation, resulting in the catalytic generation of the potent DNA-damaging agent hydroxyl radical. In the absence of reductants, H2O2 can interact with Cr(pic)3 to produce hydroxyl radicals by a second, less efficient mechanism. Cr(pic)3 is extremely stable, which allows the complex to be readily absorbed but also to potentially be incorporated into cells intact. In this form, Cr(pic)3 is primed by its redox potential to enter into the generation of hydroxyl radicals. This study suggests that investigation of the long-term effects of supplementation of the diet with Cr(pic)3 are needed to assess the safety of this material.
3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an alpha-picoline derivative with anti-tumour activity in preclinical models. Penclomedine administration by 1-h intravenous infusion on 5 consecutive days was repeated 3 weekly in the absence of dose-limiting toxicity (DLT) or disease progression. Five dose levels were investigated (22.5-340 mg m(-2) day[-1]). Eight men and eight women were entered, median age 59 years (range 39-73 years), with good performance status (ECOG 0/1) in 11 patients. A total of 13 out of 16 patients had received previous chemotherapy. Common toxicity criteria grade (CTCg) II vomiting was recorded at all dose levels. Neurotoxicity (cerebellar ataxia and dizziness) was the DLT, CTCg III toxicity occurring in three out of three patients treated at 340 mg m(-2) day(-1). CTCg III dizziness was noted in one out of three patients at 250 mg m(-2) day(-1). Neurotoxicity developed during the 1-h infusion and persisted for a variable period (maximum 5 h) after infusion. Prophylactic antiemetic drugs appeared to reduce associated vomiting but did not prevent ataxia. No antiproliferative toxicities were noted and no anti-tumour responses were documented. Penclomedine pharmacokinetic studies confirmed preclinical evidence of extensive apparent distribution (93 l m[-2]) and rapid clearance (41 l h[-1] m[-2]). Purkinje cell loss has been identified in preclinical models after intraperitoneal administration (O'Reilly et al, 1996a) and further clinical development of penclomedine will focus on oral administration.
Alpha-picolinic acid (PA), a metabolite of tryptophan and an inducer of apoptosis in the animal cell, has been reported to be a toxin produced by some of plant fungal pathogens and used in screening for disease resistant mutants. Here, we report that PA is an efficient apoptosis agent triggering cell death of hypersensitive-like response in planta. Confirmed by Fluorescence Activated Cell Sorter (FACS), rice suspension cells and leaves exhibited programmed cell death induced by PA. The PA-induced cell death was associated with the accumulation of reactive oxygen species that could be blocked by diphenylene iodonium chloride, indicating that the generation of reactive oxygen species was NADPH-oxidase dependent. We also demonstrated the induction of rice defense-related genes and subsequent resistant enhancement by PA against the rice blast fungus Magnaporthe grisea. Hence, it was concluded that the PA-stimulated defense response likely involves the onset of the hypersensitive response in rice, which also provides a simple eliciting tool for studying apoptosis in the plant cell.
Macrophage (Mphi)-based vectors are highly mobile cellular shuttles designed to deliver therapeutic genes within the tissues. We engineered a mouse Mphi cell line to express the murine interferon-gamma (IFNgamma) under the control of an inducible promoter containing the hypoxia-responsive element, which can be triggered by hypoxia and other stimuli. We show that this Mphi vector can be induced to produce IFNgamma under normoxic conditions by stimulation with picolinic acid (PA), a catabolite of tryptophan, or desferrioxamine (DFX), an iron-chelating drug. The Mphi vector responds to IFNgamma with the induction of IRF-1 and of other IFNgamma-inducible genes, the expression of Ia antigens and induction of phagocytic activity. Inducible nitric oxygen synthase gene expression, nitric oxide production, as well as TNFalpha secretion were enhanced by PA or DFX as the sole stimuli. None of the above responses could be triggered individually by PA or DFX in control, normal Mphi, indicating that the Mphi vector overcame the need for costimulatory molecules derived from the immune system for its full activation. Furthermore, we demonstrate that extracellular iron can downregulate such response, thereby identifying an additional tool for the fine tuning of the Mphi vector response to stimulation.
The Gif family of catalysts, based on an iron salt and O2 or H2O2 in pyridine, allows the oxygenation of cyclic saturated hydrocarbons to ketones and alcohols under mild conditions. The reaction between [Fe(pic)3] and hydrogen peroxide in pyridine under GoAgg(III)(Fe(III)/Hpic catalyst) conditions was investigated by UV-visible spectrophotometry. Reactions were monitored at 430 and 520 nm over periods ranging from a few minutes to several hours at 20 degrees C. A number of kinetically stable intermediates were detected, and their relevance to the processes involved in the assembly of the active GoAgg(III) catalyst was determined by measuring the kinetics in the presence and absence of cyclohexane. EPR measurements at 110 K using hydrogen peroxide and t-BuOOH as oxidants were used to further probe these intermediates. Our results indicate that in wet pyridine [Fe(pic)3] undergoes reversible dissociation of one picolinate ligand, establishing an equilibrium with [Fe(pic)2(py)(OH)]. Addition of aqueous hydrogen peroxide rapidly generates the high-spin complex [Fe(pic)2(py)(eta1-OOH)] from the labilised hydroxy species. Subsequently the hydroperoxy species undergoes homolysis of the Fe-O bond, generating HOO. and [Fe(pic)2(py)2], the active oxygenation catalyst.
This experiment was conducted to evaluate the effects of chromium (chromium picolinate) on performance and plasma concentrations of insulin and corticosterone of laying hens (Ross Brown) under a low ambient temperature (6.9 degrees C). One hundred and twenty laying hens (46 weeks old) were divided into four groups, 30 hens per group. The laying hens were fed either a control diet containing 710.3 p.p.b. chromium or the control diet supplemented with 100, 200 or 400 microg chromium/kg diet. Increasing supplemental chromium increased live weight change (p < or = 0.001, linear) and egg production (p < or = 0.001, linear) and also improved feed efficiency linearly (p < or = 0.001). Live weight change and egg production also had quadratic responses (p < or = 0.001) to increasing chromium supplementation. Plasma insulin concentration increased linearly (p < or = 0.001), whereas corticosterone concentration decreased linearly (p < or = 0.001) as dietary chromium supplementation increased. The results of this study indicate that supplemental dietary chromium, 200 p.p.b. in particular, had a positive effect on performance and increased the plasma insulin concentration of laying hens under cold stress.
Chromium (Cr) is essential for the regulation of insulin action, and Cr supplementation has been studied as a potential therapy of insulin resistance and lipid abnormalities. Corticosteroid treatment is well known to cause the abnormality of carbohydrate metabolism. Recently, it has been reported that corticosteroid increases urinary loss of Cr, and Cr supplementation recovers steroid-induced diabetes mellitus. In this experiment, rats were treated daily with dexamethasone (DEX) (0.2 mg/kg, intraperitoneal [IP]) for the first 7 days and were further treated with DEX plus either chromium picolinate (CrP, 30 mg/kg/d) orally or a placebo for a period of 14 days. At the end of experiment (D21), the control rats, which were treated only with DEX weighed 320 g (80% of initial weight) on average, but CrP-treated rats weighed 364 g (91% of initial weight. P <.05). Glucose tolerance tests (GTTs) and insulin sensitivity tests were conducted. During insulin sensitivity tests, the area under the curve (AUC(0-->120)) of the time-glucose concentrations curves in CrP-treated group were decreased compared with those in the control group (271.4 +/- 74.9 v 1,097.4 +/- 722.2 mmol/L/min, P <.01). Fasting serum insulin levels in CrP-treated rats were clearly decreased by 46.9% compared with those in the control group (0.52 +/- 0.19 v 0.98 +/- 0.36 nmol/L, P <.05). During the GTTs, the AUC(0-->120) for time-glucose concentrations curves in CrP-treated group was not significantly different from the control group, but the AUC(0-->120) of serum insulin concentrations in the CrP-treated group were 55.8% lower than those in the control group (123.1 +/- 42.5 v 278.2 +/- 59.1 nmol/L/min, P <.01). The mean AUC(0-->120) of time-cholesterol concentration curves during GTTs did not significantly differ between the 2 groups (867.6 +/- 155.2 v 827.7 +/- 94.3 mmol/L/h, P = not significant [NS]). In contrast, 1-hour and 2-hour plasma triglycerides were significantly lower in the CrP-treated group, and the mean AUC of the time-triglyceride curve was significantly lower in CrP-treated group than in the control group (3.4 +/- 0.5 v 5.9 +/- 1.3 mmol/L/h, P <.05). We suggest that Cr supplementation in DEX-treated rats can relatively reverse a catabolic state and increase insulin sensitivity. Our results support the hypothesis that Cr supplementation can be considered to improve carbohydrate and lipid metabolism in patients receiving corticosteroid treatment.
The nutritional dietary supplement chromium picolinate, [Cr(pic)(3)], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic)(3)] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic)(3)] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster. [Cr(pic)(3)], but not CrCl(3), at levels of 260 microg Crkg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility.
This experiment was conducted to evaluate the effects of chromium (chromium picolinate, Cr Pic) and vitamin C (L-ascorbic acid) supplementation on egg production and egg quality in laying hens (Hy-Line) kept at 18 degrees C (at thermo-neutral zone) or 6 degrees C (cold stress) in temperature-controlled rooms. One hundred and fifty laying hens (32 week-old) were divided into 5 groups, 30 hens per group. The laying hens kept at 6 degrees C temperature were fed either a basal diet (low temperature-basal diet, LTB group) or the basal diet supplemented with either 400 micrograms of Cr per kg diet (Cr group), 250 mg of L-ascorbic acid per kg diet (Vit C group) or 400 micrograms of Cr plus 250 mg of L-ascorbic acid per kg diet (Vit C + Cr group) while hens kept at 18 degrees C fed a basal diet (thermo-neutral-basal diet, TNB group). Performance and egg quality were significantly reduced in LTB group compared with TNB group. Supplemental chromium and vitamin C significantly increased live weight change, egg production, and improved feed efficiency in cold-stressed hens compared with group fed the basal diet at 6 degrees C brought up to the values of the group reared under thermoneutral conditions (18 degrees C). Egg production and egg weight were also greater in each supplemental group compared with the LTB group. Separately or as a combination, supplemental chromium and vitamin C increased serum insulin but decreased corticosterone, glucose and cholesterol concentrations. Results of the present study show that supplementing vitamin C and chromium, particularly as a combination, improved the performance of cold-stressed hens. Such a combination of supplement can offer a potential protective management practice in preventing cold stress-related losses in performance of laying hens.
Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [3H]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [3H]PA. After 4 h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [3H]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [3H]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.
Chromium (Cr) picolinate (CrPic) is a widely used nutritional supplement for optimal insulin function. A relationship among Cr status, diabetes, and associated pathologies has been established. Virtually all trials using CrPic supplementation for subjects with diabetes have demonstrated beneficial effects. Thirteen of 15 clinical studies (including 11 randomized, controlled studies) involving a total of 1,690 subjects (1,505 in CrPic group) reported significant improvement in at least one outcome of glycemic control. All 15 studies showed salutary effects in at least one parameter of diabetes management, including dyslipidemia. Positive outcomes from CrPic supplementation included reduced blood glucose, insulin, cholesterol, and triglyceride levels and reduced requirements for hypoglycemic medication. The greater bioavailability of CrPic compared with other forms of Cr (e.g., niacin-bound Cr or CrCl(3)) may explain its comparatively superior efficacy in glycemic and lipidemic control. The pooled data from studies using CrPic supplementation for type 2 diabetes mellitus subjects show substantial reductions in hyperglycemia and hyperinsulinemia, which equate to a reduced risk for disease complications. Collectively, the data support the safety and therapeutic value of CrPic for the management of cholesterolemia and hyperglycemia in subjects with diabetes.
Picolinic acid (PA) was measured by high pressure liquid chromatography in human milk and other fluids and tissues. Skimmed human milk, intestinal homogenates from human infants and rats, and human and rat pancreatic juice were ultrafiltered and analyzed by high pressure liquid chromatography using an anion-exchange column. Identity of sample components was verified by comparing retention times with those of pure nicotinic acid and PA. The detection limit for PA was 2.5 microM. Human milk contained less than 3.7 microM PA. PA was undetectable in human infant or rat intestine or in human or rat pancreatic juice. The extremely low concentration of PA in milk and its apparent absence in pancreatic juice and intestine provide additional evidence that PA is not the low molecular weight zinc binding ligand of human milk and that it does not have an important physiological role in intestinal zinc absorption.
In five experiments, rats were fed tryptophan (Tryp)-deficient diets with 6-12 micrograms/g zinc (Zn) and, in one experiment, a Zn-deficient diet to test the effect on clinical manifestations, plasma and bone Zn, and ability of picolinic acid (PA) or extra (12 micrograms/g) Zn to compensate. Tryp deficiency caused classical manifestations of pellagra although niacin intake was in excess of normal requirements. At marginal Zn intakes, oral PA caused a significant increase of plasma Zn and, compared with Tryp-adequate controls, Tryp deficiency resulted in lower plasma Zn and plasma:bone Zn ratios. Extra Zn (total 24 micrograms/g) was ineffective. Subcutaneous PA showed a tendency to lower plasma Zn. PA had no effect on clinical manifestations. We conclude that a Tryp metabolite other than nicotinic acid is necessary in the prevention of pellagra. Our hypothesis links this finding with the observed Tryp and PA effect on Zn metabolism.
OBJECTIVES: A natural metal ion chelator, picolinic acid (PA), is known to potentiate macrophage antimycobacterial activity. Here, we studied the antimicrobial activity of PA against extracellular and intramacrophage Mycobacterium avium complex (MAC) organisms. METHODS: MAC organisms, MAC-infected macrophages or MAC-infected type II pneumocytes were cultured in the presence or absence of PA with or without antimycobacterial drugs, and residual bacterial cfu of extracellular or intracellular MAC were counted on 7H11 agar plates. RESULTS: First, PA exhibited antimicrobial activity against extracellular and intramacrophage MAC. The effect of PA was mimicked by other metal ion-chelating agents, such as ethylenediamine tetraacetic acid and O,O'-bis (2-aminophenyl) ethyleneglycol-N,N,N',N'-tetraacetic acid. Second, PA potentiated antimicrobial effects of a two-drug combination of clarithromycin/rifampicin and some fluoroquinolones (levofloxacin, sitafloxacin and gatifloxacin) against extracellular and intramacrophage MAC. Similar combined effects of PA with clarithromycin/rifampicin were also seen in the case of MAC residing within type II alveolar epithelial cells. CONCLUSIONS: PA exerted an appreciable anti-MAC activity, when used singly or in combination with some antimycobacterial drugs (clarithromycin/rifampicin and fluoroquinolones), suggesting the usefulness of PA as an adjunct for clinical antimicrobial chemotherapy of MAC infections.
Young male Sprague-Dawley rats were divided in 18 groups of eight animals each and were fed ad libitum for 24 d a purified diet with 20% casein, whey protein or serum albumin as protein source. Each diet was supplemented with zinc picolinate, zinc citrate or zinc sulfate to a level of dietary zinc equal to 5 or 10 ppm. The source of zinc had no significant effect on zinc utilization with any of the three dietary proteins or at either dietary zinc concentration. With the 5 ppm Zn diet zinc concentration in the serum, but not weight gain or the zinc concentration in femur, testis or whole body was lower in rats fed the casein diet than in those fed the whey diet. Zinc concentrations in serum, femur, testis and whole body, but not weight gain, were lower in rats fed the casein diet than in those fed the serum albumin diet. With the 10 ppm Zn diet, zinc concentrations in serum, femur and whole body, but not weight gain nor zinc concentration in testis, were lower in rats fed the casein diet than in those fed either of the other diets. These results suggest that the reason for the lower utilization of zinc from cow milk in comparison to human milk may be the higher casein concentration in cow milk.
Twenty weanling pigs and fourteen 9-wk-old broiler chickens were used in three continuous-flow in vitro perfusion experiments using noneverted intestinal sacs to 1) determine differences in 65Zn absorption due to location within the intestinal tract, 2) evaluate 65Zn uptake from ZnCl2 and Zn-methionine (ZnMet) with or without added picolinic acid (PA) in pig intestinal sacs and 3) evaluate 65Zn uptake from ZnCl2 and ZnMet in chicken intestinal sacs. No differences in 65Zn uptake due to gut segment position were observed in the pigs. A Zn source x PA interaction was observed for 65Zn uptake into the pig gut tissue and for 65Zn uptake to the serosal side of the gut sacs. Total 65Zn absorption in the pig gut sacs from the two Zn sources was not different, but the addition of a 5 M ratio of PA to Zn depressed 65Zn absorption. No differences were observed in total 65Zn absorption or 65Zn uptake in poultry gut sac tissue. There was, however, greater uptake of 65Zn from ZnCl2 to the serosal side of the sacs than from ZnMet. The data indicate that 65Zn from ZnCl2 and ZnMet is similar in total absorption and that the addition of PA depresses Zn uptake.