Structure-stability Relationship Research Articles

In vitro and in vivo evaluation of structure-stability relationship of 111In- and 67Ga-labeled antibody via 1B4M or C-NOTA chelates

2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (C-NOTA) or 2-(p-isothiocyanatobenzyl) -6-methyl-diethylenetriamine pentaacetic acid (1B4M) was conjugated to monoclonal antibody T101 (IgG2a), radiolabeled with 111In or 67Ga and then purified through size-exclusion HPLC. 111In 1B4M-T101 and 67Ga C-NOTA-T101 were stable in in vitro serum at 37 °C. In contrast, 111In C-NOTA-T101 and 67Ga 1B4M-T101 were unstable. The biodistribution in normal mice reflected the instability of the metal complex; the less-stable 111In C-NOTA conjugate left less tracer in blood, but more in liver and kidney whereas the less-stable 67Ga 1B4M conjugate left less tracer in blood, but more in bone. The biodistribution data suggest that the difference shown between the 111In and 67Ga conjugates might be mediated by differences in the in vivo chemistry of the metallic ions.

Thermal degradation of segmented polyurethanes

AbstractThermal degradation of polyurethane samples was studied by a thermogravimetric method. The effect of soft‐segment length and soft‐segment concentration on activation energy of the degradation process was measured. Three methods of calculation gave activation energies at different stages of the very complex weight loss process. It was shown that at initial stages of the weight loss the process was dominated by hard‐segment degradation. Activation energy of the whole process calculated by the Ozawa–Flynn method did not offer clear insight into the structure–stability relationship of polyurethanes. The second method showed that activation energy of the initial stage of degradation increased with decrease in hard‐segment length. The Flynn method of calculating activation energy produced fairly constant activation energy of the first 40% degradation, at around 150 kJ/mol, for polymers in the C series. Generally, calculation of kinetic parameters of a complex degradation process as in polyurethanes gives results that are not easy to interpret. It has been shown qualitatively that polymers with higher soft‐segment concentration display lower initial weight loss and higher onset temperatures of degradation. © 1994 John Wiley & Sons, Inc.

Quantitative structure-stability relationship for potassium ion complexation by crown ethers. A molecular mechanics and ab initio study

Molecular mechanics calculations with the MM2 program were used to examine the structures and strain energies 11 hexadentate crown ether ligands and their potassium complexes. With the exception of K-O stretching parameters, all force field parameters for interactions involving the potassium ion were obtained by fitting to ab initio potential energy surfaces for selected distortions in K-O(Me)[sub 2] and K-O(Me)(Et). The K-O stretching parameters were optimized relative to crystallographic data. Comparison of the molecular mechanics results to experimental log K values that were available for all 11 crown ethers revealed the complex stability to be strongly correlated with the difference in strain energy between the uncomplexed ligand and its potassium complex. The results establish that both the K-O length preference and bonding directionality at the ether oxygen donor atom are important factors in the determination of complex stability. It is concluded that the failure to consider the orientation of the ether C-O-C moiety, relative to the metal ion, is a serious flaw in the size-match selectivity theory. 78 refs., 9 figs., 4 tabs.

Thermodynamic nucleic base specificity in nucleotide-metallointercalator association. Structure-stability relationship showing significant contribution of the amino group to aromatic ring stacking

Thermodynamic nucleic base specificity in nucleotide-metallointercalator association. Structure-stability relationship showing significant contribution of the amino group to aromatic ring stacking

Structure-stability relationship of Immobiline chemicals for isoelectric focusing as monitored by capillary zone electrophoresis

An acrylamido buffer for isoelectric focusing in immobilized pH gradients, 1-acryloyl-4-methylpiperazine (p K = 6.85 at 25°C), was synthesized. As it is a disubstituted amide, it was thought that it would be much more resistant to alkaline hydrolysis. In reality, it degraded rapidly in 0.1 M sodium hydroxide solution at 70°C (86% in 6 h). Therefore, the stability of Immobiline buffers of p K 9.3, 8.5, 7.0 and 6.2 was investigated. Under the same hydrolysis condition, the degradation was 11%, 22%, 26% and 34%, in order of decreasing p K values. The kinetics of degradation were monitored by capillary zone electrophoresis in 0.1 M borate buffer (pH 9). The decrease of the main Immobiline peak and the appearance of its hydrolytic products, acrylic acid and a diamine, could be easily measured. The following general rules were derived: when the nitrogen engaged in the amido bond is inserted into a cyclic structure ( e.g., 1-acryloyl-4-methylpiperazine) there is very little protection against hydrolysis, and conversely, when this nitrogen carries flexible, fairly long substituents (4–5 atoms long) much stronger shielding and protection of the amido bond can be obtained. These findings helped in designing new acrylamido derivatives strongly resistant to chemical degradation.

Mechanism of Hydrolysis and Structure–Stability Relationship of Enaminones as Potential Prodrugs of Model Primary Amines

The objective of this work was to investigate the chemistry and the structure–stability relationship of enaminones (a class of enamines formed between a primary amine and a 1,3-dicarbonyl compound) and to evaluate their potential usefulness as prodrugs of primary amines. The acid-catalyzed degradation of the enaminones was found to be very sensitive to minor differences in the structure of the 1, 3-dicarbonyl compound used to form the enaminone, but relatively insensitive to changes in the amine portion of the enaminones. A correlation was found between the rate of enaminone hydrolysis and the pKa of the 1,3-dicarbonyl compound, suggesting that the rate-controlling step in the hydrolysis of the enaminones was the proton addition to the vinyl carbon of the enaminone. Enaminones formed with cyclic 1, 3-dicarbonyl compounds were significantly more stable than those formed with structurally similar acyclic compounds. Based on chemical stability considerations alone, enaminones do not appear to be good candidates as prodrugs of primary amines. Evidence is presented, however, that enaminones formed between amines and 1,3-ketoesters or lactones may be subject to enyzme-catalyzed degradation. Further research on the design of enaminones destabilized by a triggering enzymatic event that results in the loss of conjugation (e.g., ester or lactone hydrolysis or an oxidation/reduction event) may prove worth pursuing.

Quantitative study of the structure-stability relationship of Tc vO(III) complexes

This paper describes the quantitative structure-stability relationship of Tc vON 2S 2 compounds using a stability indicator based on the solid angle factor sum (SAS)_for predicting the in vitro stability. The SAS values of six Tc vON 2S 2 and one Tc vON 4 ( d,l-HMPAO) complexes were calculated from their x-ray crystallography data. The rank order of in vitro stability of these compounds, as measured by ligand exchange reaction, is directly related to that of the SAS values. The SAS values are potentially useful for predicting stability and designing new 99mTc radiopharmaceuticals.

Quantitative study of the structure-stability relationship of Tc complexes

By studying structural parameters (van der Waals radius and bond length from x-ray crystallography) of more than 100 known Tc compounds and using the cone packing model, a stability indicator of the Tc compounds was derived. The indicator is based on the solid angle factor sum (SAS), which is calculated from van der Waals radii and bond lengths between all coordinating atoms and Tc. The average SAS value is 0.97 ± 0.13. The SAS value reflects the limits of the packing of ligand around Tc. The quantitative calculation of the SAS is useful for predicting stability and designing new Tc radiopharmaceuticals.

Degradation kinetics of (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HY-770) and structure-stability relationship among its analogues in aqueous solution.

The kinetics and pathways for degradation of (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HY-770; 1), a newly developed muscle-relaxing agent, and its analogues were studied in aqueous solution at 50 degrees C, ionic strength 0.5 M, and pH 8.0-12.0. Compound 1 and its four analogues followed pseudo-first-order degradation kinetics at constant pH and temperature. From the analysis of the pH degradation-rate profiles, it is evident that specific hydroxide ion-catalyzed degradations of ionized and un-ionized species occur for 1 and its structural analogue, 3'-fluoro-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HN-961; 5). The hydroxide ion-catalyzed degradation of the ionized species was found to be 100 times faster than that of the un-ionized species and to be the major process at pH less than 9.0. On the contrary, 1 was extremely stable in 0.5 M HCl at 50 degrees C, suggesting that the hydronium ion-catalyzed degradation and the spontaneous degradation of the ionized species is negligible. The Arrhenius plot for the degradation of 1 at 35-50 degrees C and pH 9.0 showed that the apparent energy of activation was 22.0 kcal/mol. The degradation rates of the five structural analogues were significantly dependent on the electron withdrawing effect of the benzene substituents of the molecule.

Structure-stability relationship in proteins: fundamental tasks and strategy for the development of stabilized enzyme catalysts for biotechnology.

The problem of relationships between the protein structure and its stability comprises two major questions. First, how to elucidate the peculiarities of the protein structure responsible for its stability. Second, knowing the general molecular basis of protein stability, how to change the structure of a given protein in order to increase its stability. This review is an attempt to show the modern state of the first (fundamental) and the second (applied) aspects of the problem.

Structure-stability relationship of copper(II)-indol carboxylic acid derivative complexes from spectrophotometric, thermogravimetric and potentiometric studies

Some copper(II) complexes of N-methyl indol carboxylic acid derivatives have been isolated and characterized. These complexes were subjected to elemental and thermogravimetric analyses together with UV, visible and IR spectral studies. Based on these physicochemical studies, the suggested formula for the complexes obtained is CuL 2 where L = N-methyl indol carboxylic acid derivatives L 1- 4. Thermogravimetric analyses of the isolated complexes have already indicated different modes of interaction between the ligands and the central copper(II) metal ions. UV, visible and IR spectral studies have indicated that coordination of the ligands to the central metal ion is via carboxylic-, hydroxyl- and/or nitrogen-containing groups. The stability constants of some of these metal chelates were determined from potentiometric measurements and found to be in the order Cu(L 3) 2 < Cu(L 2) 2 < Cu(L 4) 2, which essentially depends on the acid dissociation constants of the ligands, determined under the same conditions.

Structure-stability relationship in ternary copper(II) complexes involving aromatic amines and tyrosine or related amino acids. Intramolecular aromatic ring stacking and its regulation through tyrosine phosphorylation

Evaluation de la stabilisation due a la liaison non covalente intramoleculaire entre les chaines laterales d'un aminoacide et une diamine dans un complexe ternaire de Cu(II)

Stability of Fused Rings in Metal Chelates. XI. Stability of Dipeptide Amide-Copper(II) Complexes

Abstract The structure-stability relationship between the copper(II) complexes of several dipeptide amides consisting of glycine and/or β-alanine has been investigated by potentiometric titration. The amides of glycylglycine, glycyl-β-alanine, and β-alanylglycine (abbreviated as H2L) have been found to form complexes of the type Cu(H2L)2+ with logK1 values 4.80–5.22. The −logKC1 values for deprotonation of the peptide group are 5.05–5.42 and comparable to those of tripeptides, whereas the −logKC2 values for the terminal amide group are 7.96 for glycylglycine amide and 8.99 for glycyl-β-alanine amide. This indicates that, at neutral pH, the –CONH2 group coordinates to copper(II) mainly through the carbonyl oxygen. β-Alanyl-β-alanine amide-copper(II) system gave precipitates at an early stage of titration. The structures and relative stability of the complexes of types Cu(H2L)2+, Cu(HL)+, and CuL have been discussed from comparative studies of their stability constants.

Stability of Fused Rings in Metal Chelates. X. Structures and Stability Constants of the Copper (II) Complexes of Tripeptides Composed of Glycine and/or β-Alanine

Abstract On the basis of comparative studies of the equilibria involving copper(II) and triglycine (G·G·G), glycylglycyl-β-alanine (G·G·β-A), glycyl-β-alanylglycine (G·β-A·G), or β-alanylglycylglycine (β-A·G·G), the structures of the complexes formed at various pH values and the structure-stability relationship between the fusedring chelates have been discussed in reference to the equilibrium constants determined by potentiometric titration at 25°(μ=0.1 (KNO3)) and the properties of the copper(II) chelates isolated. For each tripeptide, the stability constant K1 for the 1: 1 complex and the constants for the deprotonation reactions Kc1 and Kc2 were calculated by the method of non-linear least-squares. For G·G·G, G·G·β–A, and G·β–A·G, the equilibrium indicating the formation of a protonated complex was detected at pH 3.5–4.5. The relatively small difference in the logK1 values (5.25–5.60) and the logKc1 values (5.23–5.36) and the larger difference in the −logKc2 values (5.54–6.73) have been interpreted in terms of the steric requirements around copper(II) in the fused-ring chelates. Relative stabilities of the fused-ring systems in the deprotonated chelates have been inferred from the K1Kc1Kc2 values to be in the order 5-6-5(G.β-A·G-Cu(II))\simeq6-5-5(β-A·G·G-Cu(II))&amp;gt;5-5-6(G·G·β-A-Cu(II))&amp;gt;5-5-5(G·G·G–Cu(II)).

The Structure-Stability Relationship of the Metal Ion Complexes of Unsaturated Compounds. V. Stabilities of the Silver-Ion Complexes of Some cis-Stable Olefins

Abstract The silver-ion complexation equilibria of a few cis-stable olefins have been investigated in an aqueous phase at 25°C. The trans isomers of β-chlorovinyl ethyl ether and 1,2-dichloroethylene were found to have greater equilibrium constants than the corresponding cis isomers. It was concluded that the relative stabilities of parent olefin isomers play an exclusive role determining their relative complexation abilities.

The Structure-Stability Relationship of the Metal Ion Complexes of Unsaturated Compounds. IV. Argentation Equilibria of Alkenyl Alkyl Ethers

Abstract The equilibrium constants, K, for the formation of 1 : 1 Ag+ - alkenyl alkyl ether complexes were measured in the temperature range 10 to 30°C by the gas chromatographic method. It has been found (1) that cis isomers have the values of K several times greater than those of the corresponding trans isomers, (2) that the K-value tends to diminish with the increasing degree of β-substitutions, (3) that, in a series of cis ethers, K increases as the β-alkyl substituent becomes bulkier, and (4) that the variation of the alkoxy groups causes little change in the K-value. The difference in the K-values between the cis and trans complexes is found to be ascribable mainly to their difference in the enthalpy changes, ΔH, accompanying the complexation. These trends have been discussed on a thermodynamic ground in comparison with those already noted for olefins.

The Structure-Stability Relationship of the Metal Ion Complexes of Unsaturated Compounds. III. The Effects of Polar Substituents on the Silver Ion - Olefin Complexation

Abstract The equilibrium constants for the formation of silver ion complexes of various vinyl compounds in water were determined at 25°C by the distribution method. It has been found that the equilibrium constants obtained are closely related to the Hammett sigma meta values of the relevant substituents, the reaction constant being ρ=−5.07 with the correlation coefficient r=0.974. The results have been interpreted in terms of the inductive effect of the substituents as the most dominant contribution to the stabilities of these complexes.