Mario Ciampolini

Small aza cages as “fast proton sponges” and strong lithium binders

The design and synthesis of new compounds in order to achieve expected or new chemical properties is one of the most fascinating aspects of modern synthetic chemistry. Among the many thousands of new compounds synthesized each year, macrocyclic compounds play an important role. The ever growing interest in this very active field stems from different points of view, including selective ion recognition, transport processes, reaction catalysis, industrial applications, model systems, and others [l-17]. Numerous books on macrocyclic chemistry have been published in the last few years [18-27]. Molecular topology and the nature of donor atoms are the two most important parameters influencing the chemical properties of macrocyclic compounds. Different classes of synthetic macrocyclic compounds have been developed and, in addition to the most studied crown-ether family, the aza-crowns are the next most studied class of synthetic macrocycles [ 19,251. These compounds could be considered to be derived from crown ethers by replacing the oxygen donor atoms with softer nitrogen donor atoms. The presence of this kind of donor atom makes these compounds water soluble bases and very prone to bind transition metal ions [28,29].

Training to estimate blood glucose and to form associations with initial hunger

BackgroundThe will to eat is a decision associated with conditioned responses and with unconditioned body sensations that reflect changes in metabolic biomarkers. Here, we investigate whether this decision can be delayed until blood glucose is allowed to fall to low levels, when presumably feeding behavior is mostly unconditioned. Following such an eating pattern might avoid some of the metabolic risk factors that are associated with high glycemia.ResultsIn this 7-week study, patients were trained to estimate their blood glucose at meal times by associating feelings of hunger with glycemic levels determined by standard blood glucose monitors and to eat only when glycemia was < 85 mg/dL. At the end of the 7-week training period, estimated and measured glycemic values were found to be linearly correlated in the trained group (r = 0.82; p = 0.0001) but not in the control (untrained) group (r = 0.10; p = 0.40). Fewer subjects in the trained group were hungry than those in the control group (p = 0.001). The 18 hungry subjects of the trained group had significantly lower glucose levels (80.1 ± 6.3 mg/dL) than the 42 hungry control subjects (89.2 ± 10.2 mg/dL; p = 0.01). Moreover, the trained hungry subjects estimated their glycemia (78.1 ± 6.7 mg/dL; estimation error: 3.2 ± 2.4% of the measured glycemia) more accurately than the control hungry subjects (75.9 ± 9.8 mg/dL; estimation error: 16.7 ± 11.0%; p = 0.0001). Also the estimation error of the entire trained group (4.7 ± 3.6%) was significantly lower than that of the control group (17.1 ± 11.5%; p = 0.0001). A value of glycemia at initial feelings of hunger was provisionally identified as 87 mg/dL. Below this level, estimation showed lower error in both trained (p = 0.04) and control subjects (p = 0.001).ConclusionSubjects could be trained to accurately estimate their blood glucose and to recognize their sensations of initial hunger at low glucose concentrations. These results suggest that it is possible to make a behavioral distinction between unconditioned and conditioned hunger, and to achieve a cognitive will to eat by training.

Complexes of cobalt(II), nickel(II), copper(II), and zinc(II) with the tripod-like ligands tris (2-methylthioethyl)amine

Abstract The preparation and properties of nine complexes formed by the quadridentate ligand tris(2-methylthioethyl)amine, TSN, and the halides or thiocyanate of cobalt(II), nickel(II), copper(II), and zinc(II) have been studied. The cobalt complexes are formulated as [CoX(TSN)] 2 [CoX 4 ] thus containing both high-spin five-coordinated cobalt and tetrahedral cobalt. The compounds NiX 2 (TSN) are octahedral and [CuBr(TSN)]Br is five-coordinated. Zinc iodide forms the monomeric compound Znl 2 (TSN).

Differences in maintenance of mean blood glucose (BG) and their association with response to “recognizing hunger”

Background: Meals begin and end subjectively. We trained healthy subjects to recognize initial hunger as a preprandial target for meal consumption, and to create a “recognizing hunger” or initial hunger meal pattern. Objective: Training subjects to “recognize hunger” lowers blood glucose (BG) and improves energy balance, and lowers metabolic risks and bodyweight. A minority may have low BG and low metabolic risks at recruitment, but the others may recover this favorable condition by training. Methods: In a 7-day food diary, subjects reported their preprandial BG measurements; BG and energy availability by blood were assessed at the lowest BG during the day, and diary-mean BG thus characterized the individual meal pattern (daily energy intake). We analyzed the same diaries of a recent paper on a global, randomized comparison of subjects trained in “recognizing hunger” with control subjects. This time, we checked whether subjects who had maintained low BG (LBG subgroup) at recruitment were able to decrease mean BG and metabolic risk factors during “hunger recognition” like those who presented high BG (HBG subgroup). Results: At recruitment, the BG means of 120 investigated subjects were within mean confidence limits of ± 3.84 mg/dL, and we could stratify subjects in ten small strata of which each significantly differed by mean BG. Mean BG was stable in each control subject over five months; the mean absolute change being 6.0 ± 4.6 mg/dL. Only three out of 34 trained subjects who had lower mean BG than 81.8 mg/dL significantly decreased mean BG, whereas 41 out of 55 subjects whose mean BG was greater than 81.8 mg/dL significantly decreased mean BG after training (P < 0.0001). At recruitment, the LBG subgroup showed significantly lower insulin, lower BG area under curve (AUC) in the oral glucose tolerance test (GTT), and lower HbA1c than the HBG group. After training, only HBG subjects, compared with HBG controls, significantly decreased preprandial BG from 91.6 ± 7.7 mg/dL to 81.0 ± 7.7 mg/dL, in association with a decrease of HbA1c from 4.81% ± 0.44% to 4.56% ± 0.47%, of GTT insulin AUC from 244 ± 138 mU/L to 164 ± 92 mU/L, and of energy intake from 1872 ± 655 kcal to 1251 ± 470 kcal (P < 0.001), with an increase of indices of insulin sensitivity from 5.9 ± 3.3 to 9.8 ± 5.6 and of beta cell function from 1.0 ± 0.7 to 1.4 ± 1.1 (P < 0.05). LBG subjects only decreased weekly-diary BG standard deviation in comparison with controls. Conclusion: At recruitment, the 120 subjects maintained mean BG at one personal level of ten possibilities, and 34 subjects were below 81.8 mg/dL (LBG) and 55 were over (HBG). The 55 HBG subjects showed higher mean insulin resistance, HbA1c, other cardiovascular risk factors, and increased bodyweight compared with the 34 LBG subjects. A total of 41 out of the 55 HBG subjects regressed to LBG with training.

Proton inclusion properties of a new azamacrocycle. Synthesis, characterization and crystal structure of [H3L][Cl]3·2H2O (L = 4,10-dimethyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane)

Abstract Macrocyclic compounds have been extensively investigated, the interest for this huge class of compounds spans from fundamental research to specific industrial applications. 1 – 8 We have recently published a few papers on small macrocycles having cage-like molecular topology.9 – 19 They present special proton-transfer properties and in few cases they are strong, selective lithium binders in aqueous solution.14,15,17 The three-dimensional cavity present in these compounds is achieved by connecting two secondary nitrogen atoms of a tetraazamacrocycle with different bridging groups (see Fig 1). Molecular topology and nature of donor atoms are the most important elements influencing the chemical properties of this class of compounds. For these reasons we are continuing our investigations on these compounds by systematically changing the bridging unit; we report here the synthesis and chemical properties of the new cage 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]-tetradecane, abbreviated as L.

Normal energy intake range in children with chronic nonspecific diarrhea: association of relapses with the higher level.

An increase in energy intake often occurs at weaning. The increase may be due partly to prompting by the caregiver to accelerate the childs weight gain and partly motivated by the palatability of common weaning foods. Increased food intakes initiated during weaning and continued into the second year of life may be associated with chronic, nonspecific diarrhea in selected children. An educational project was designed to reduce intakes augmented by either cause. Reductions were achieved by the regulation of energy-dense foods in the childs diet and reliance on the childs appetite control to determine meal size. The educational intervention was applied prospectively under nonblinded, controlled conditions. Children, 1 to 2 years of age, with chronic nonspecific diarrhea were assigned randomly to either a treatment or control group. Compliance, food consumption, preprandial glycemia, and outdoor activities were reported by the childrens mothers in four 7-day diaries; symptoms related to the childrens clinical condition and anthropometric and biochemical indices of nutritional status were noted at the beginning and end of a 7-month period. Forty-four of 53 children in the experimental group maintained compliance, and 44 of 47 children in the control group completed the follow-up. Energy intake decreased significantly by almost one-third in the experimental group. Growth, skinfold thickness measurements, and outdoor activities were similar between experimental and control groups over the 7-month period. Diarrheal episodes occurred in 6, 1, and 2 children in the experimental group at 1.5, 3, and 7 months and in 22, 18, and 15 children in the control group, respectively (p < 0.002). Twenty of 32 parameter of clinical status were more advantageous in the experimental group compared to 9 of 32 in the control group in a comparison of the mean values in the two groups at the final examination (p < 0.05). Serum folate (p < 0.001) also was significantly higher in the experimental group. The described intervention appeared to achieve lower energy intakes in a safe and reproducible manner. It may be a useful tool to prevent overeating and control signs and symptoms associated with chronic, nonspecific diarrhea.

The small cage 12,17-dimethyl-5-oxa-1,9,12,17-tetra-azabicyclo[7.5.5]nonadecane (L): its synthesis, characterization, and ‘proton sponge’ behaviour. The crystal structure of the dipicrate salt [H2(L)](picrate)2

The synthesis and characterization of the new oxa-azamacrobicycloalkane 12,17-dimethyl-5-oxa-1,9,12,17-tetra-azabicyclo[7.5.5]nonadecane (L) are described. Its basicity behaviour in both aqueous and water–Me2SO (50:50 mol/mol) solutions has been investigated by potentiometric and spectroscopic (1H and 13C n.m.r.) techniques. In aqueous solution it behaves as a very strong base (proton sponge) in the first protonation step, and as a relatively strong base in the second step (log k2= 11.21). In the mixed water–Me2SO solvent both protonation constants have been measured: log k1= 14.0 and log k2= 8.2. 1H N.m.r. experiments indicate that in the monoprotonated species H(L)+ the proton is rapidly exchanged with acidic hydrogens on the n.m.r. timescale. 1H–1H and 1H–13C two-dimensional n.m.r. experiments allowed the unequivocal assignment for all the 1H proton and 13C resonances of both species H(L)+ and H2(L)2+. Crystals of [H2(L)](picrate)2 are monoclinic, space group P21/n, with a= 12.868(8), b= 17.201(2), c= 16.614(2)A, β= 110.18(1)°, and Z= 4; final R values of 0.090 (Rw= 0.090) for 3 801 observed reflections. The four basal nitrogen atoms and the apical oxygen atom are located at the apices of a slightly distorted square pyramid. X-Ray analysis shows that protonation occurs on the NCH3, groups. Each hydrogen atom of the NH+CH3 interacts with the oxygen atom, the 0 ⋯ H distances 2.328(16) and 2.112(18)A, and with both bridgehead nitrogen atoms, the H ⋯ N distances ranging from 2.32 to 2.34 A. This arrangement makes the overall structure very stable from the thermodynamic point of view and explains the unusually high basicity of (L) in both first- and second-protonation step.

Structural aspects of the protonation of small cages. Preparation of the new aza-cage 12,17-dimethyl-1,9,12,17-tetra-azabicyclo[7.5.5]nonadecane (L). Thermodynamic studies on solution equilibria. Crystal structures of [H2L][CoCl4] and [H2L1][CoCl4] salts

The synthesis and characterization of the new aza-cage 12,17-dimethyl-1,9,12,17-tetra-azabicyclo-[7.5.5]nonadecane (L) are described. The basicity behaviour in both aqueous and water–DMSO (50 : 50, mol : mol) solutions has been investigated by potentiometric and microcalorimetric (25 °C, 0.15 mol dm–3 NaCl) techniques. L behaves, in aqueous solution, as a fairly strong base (log K1= 12.00; ΔH1⊖=–54.0 kJ mol–1; TΔS1⊖= 14.5 kJ mol–1) in the first protonation step and as a moderate base in the second step (log K2= 7.86 ΔH2⊖=–44.8 kJ mol–1; TΔS2⊖ca. 0). The enthalpic and entropic contributions are discussed in terms of molecular topology and translational entropy. The CuII ion is encapsulated by L, the electronic spectra being diagnostic of a square-planar structure. The molecular structures of the diprotonated salts [H2L][CoCl4] and [H2L1][CoCl4](L1 = 5,12,17-trimethyl-1,5,9,12,17-penta-azabicyclo[7.5.5]nonadecane) have been determined by single-crystal X-ray analysis.Crystals of [H2L][CoCl4] are orthorhombic, space group pbn21, with a= 9.311 (3)A, b= 15.480(2)A, c = 16.636(6)A, and Z= 4. Final R values of 0.043 (Rw= 0.037) for 1 358 observed reflections. X-Ray analysis shows that the protonation occurs on the N–CH3 groups. Each hydrogen atom of the NH+–CH3 interacts with the two bridgehead nitrogen atoms.The compound [H2L1][CoCl4] crystallizes in a monoclinic unit cell (space group P21) with lattice constants a= 8.877(3)A, b= 14.088(8)A, c= 10.122(5)A, β= 105.51 (4)°, and Z= 2. Final R values of 0.064 (Rw= 0.049) for 2 374 observed reflections. In this case the conformation of the diprotonated cage is different and the protonation probably occurs at one of the two methylated nitrogens and at the apical nitrogen atom.

Synthesis and characterization of an aza-cage behaving as a ‘proton sponge’. Crystal structures of its mono- and tri-protonated species

The synthesis and characterization of the new macrobicyclic cage 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.4]hexadecane L is reported. Its basicity behaviour in aqueous solution has been investigated by potentiometric (25 °C, I= 0.15 mol dm–3) and NMR (1H and 13C) techniques. It behaves as a very strong base (proton sponge) in the first protonation step, and as a moderate base in the second step (log K2= 7.8). 1H–1H and 1H–13C two-dimensional NMR experiments permitted the unequivocal assignment of all 1H proton and 13C resonances of both species HL+ and H2L2+. Furthermore NMR experiments indicate that the first protonation involves the bridgehead nitrogens. Crystals of [HL][ClO4] are orthorhombic, space group P21cn, with a= 9.044(2), b= 12.573(2), c= 16.126(3)A, and Z= 4; final R value of 0.089 (Rw= 0.086) for 1267 unique observed reflections with I > 3σ(I). X-Ray analysis shows that protonation occurs on the bridgehead nitrogen N(2) and an overall macrocyclic conformation with the all nitrogen atoms in the endoconfiguration. The short H(2)⋯(4)[1.69(1)A] and N(2)⋯ N(4)[2.75(1)A] distances indicate a strong hydrogen bond. H(2) further interacts with the other two tertiary nitrogens: H(2)⋯ N(1)[2.53(1)A] and H(2)⋯ N(3)[2.46(1)A]. This arrangement makes the monoprotonated species very stable from the thermodynamic point of view and explains the high basicity of L. Crystals of [H3L][ClO4]3 are tetragonal, space group P43212, with a= 8.498(2), b= 8.498(2), c= 32.855(8)A, and Z= 4; final R value of 0.083 (Rw= 0.093) for 1076 unique observed reflections with I > 3σ(I). The X-ray analysis shows an overall macrocyclic conformation with two nitrogen atoms in the endoconfiguration and two in exo configuration.

Hunger can be taught: Hunger Recognition regulates eating and improves energy balance

A set of spontaneous hunger sensations, Initial Hunger (IH), has been associated with low blood glucose concentration (BG). These sensations may arise pre-meal or can be elicited by delaying a meal. With self-measurement of BG, subjects can be trained to formally identify and remember these sensations (Hunger Recognition). Subjects can then be trained to ensure that IH is present pre-meal for most meals and that their pre-meal BG is therefore low consistently (IH Meal Pattern). IH includes the epigastric Empty Hollow Sensation (the most frequent and recognizable) as well as less specific sensations such as fatigue or light-headedness which is termed inanition. This report reviews the method for identifying IH and the effect of the IH Meal Pattern on energy balance. In adults, the IH Meal Pattern has been shown to significantly decrease energy intake by one-third, decrease preprandial BG, reduce glycosylated hemoglobin, and reduce insulin resistance and weight in those who are insulin resistant or overweight. Young children as well as adults can be trained in Hunger Recognition, giving them an elegant method for achieving energy balance without the stress of restraint-type dieting. The implications of improving insulin sensitivity through improved energy balance are as wide as improving immune activity.