scholarly journals Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 4009
Author(s):  
István Köteles ◽  
Károly Mazák ◽  
Gergő Tóth ◽  
Boglárka Tűz ◽  
Sándor Hosztafi

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.

Proceedings ◽  
2019 ◽  
Vol 41 (1) ◽  
pp. 48
Author(s):  
István Köteles ◽  
Sándor Hosztafi

Drugs of abuse are small molecules that typically do not induce an antibody response following the administration. To induce antibodies against these kind of molecules, structural changes have to be made to obtain so called “haptens”. The hapten must be coupled to immunogenic proteins, called “carriers”. These connected derivatives are typically drug-linker adducts, in which the linker has a terminal functional group (i.e., carboxylic acid or aliphatic amine) that forms a covalent bond with the carrier. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. Six nor-normorphine compounds were reacted with ethyl acrylate and ethyl bromoacetate. After the synthesis of the specific esters we hydrolyzed them to receive the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives. The next step was the coupling phase with glycine ethyl ester, but the reactions didn’t work or the work-up process was not accomplishable. As an alternative route the normorphine-compounds were reacted with N-chloroacetyl glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine sidechain. All of the glycine ester and the glycine carboxylic acid derivatives are under biological tests.


1980 ◽  
Vol 58 (8) ◽  
pp. 629-632 ◽  
Author(s):  
Ronald Kluger ◽  
Wing-Cheong Tsui

Methyl methanesulfonothioate (MMTS) has been used as a sulfhydryl reagent. However, it inactivates D-3-hydroxybutyrate dehydrogenase in a manner that suggests that an amino group may have reacted with the reagent. Nuclear magnetic resonance (NMR) analysis of solutions of glycylglycine, glycine ethyl ester, and imidazole with MMTS indicates that a reaction occurs which produces what is identified by its NMR signal as the methylsulfenamide of the amine. It is suggested that caution should be used when MMTS is employed where reaction with an amine could give an undesired product.


2012 ◽  
Vol 487 ◽  
pp. 43-47
Author(s):  
Sheng Hua Lv ◽  
Di Li ◽  
Qiang Cao

A polycarboxylate superplasticizer (PCs) was synthesized by copolymerization of allyl polyoxyethylene ethers (APE), acrylic acid (AA), sodium methylallyl Sulfonate (SMAS) and ethyl acrylate (EA). The effect of functional groups and branch chain on PCs properties was investigated by the test of fluidity of cement paste, retardation performance and Zeta potential of cement particles. The results showed that carboxylic groups and ethyl ester groups can improve water reducing ratio and fluidity of cement paste, and the sulfonic groups has an important contributiion to retardation performance of PCs.


1968 ◽  
Vol 109 (5) ◽  
pp. 727-736 ◽  
Author(s):  
Sybil P. James ◽  
D. A. Jeffery ◽  
Rosemary H. Waring ◽  
P. B. Wood

1. Rabbits and rats dosed with 1-bromobutane excrete in urine, in addition to butylmercapturic acid, (2-hydroxybutyl)mercapturic acid, (3-hydroxybutyl)mercapturic acid and 3-(butylthio)lactic acid. 2. Although both species excrete both the hydroxybutylmercapturic acids, only traces of the 2-isomer are excreted by the rabbit. The 3-isomer has been isolated from rabbit urine as the dicyclohexylammonium salt. 3. 3-(Butylthio)lactic acid is formed more readily in the rabbit; only traces are excreted by the rat. 4. Traces of the sulphoxide of butylmercapturic acid have been found in rat urine but not in rabbit urine. 5. In the rabbit about 14% and in the rat about 22% of the dose of 1-bromobutane is excreted in the form of the hydroxymercapturic acids. 6. Slices of rat liver incubated with S-butylcysteine or butylmercapturic acid form both (2-hydroxybutyl)mercapturic acid and (3-hydroxybutyl)mercapturic acid, but only the 3-hydroxy acid is formed by slices of rabbit liver. 7. S-Butylglutathione, S-butylcysteinylglycine and S-butylcysteine are excreted in bile by rats dosed with 1-bromobutane. 8. Rabbits and rats dosed with 1,2-epoxybutane excrete (2-hydroxybutyl)mercapturic acid to the extent of about 4% and 11% of the dose respectively. 9. The following have been synthesized: N-acetyl-S-(2-hydroxybutyl)-l-cysteine [(2-hydroxybutyl)mercapturic acid] and N-acetyl-S-(3-hydroxybutyl)-l-cysteine [(3-hydroxybutyl)mercapturic acid] isolated as dicyclohexylammonium salts, N-toluene-p-sulphonyl-S-(2-hydroxybutyl)-l-cysteine, S-butylglutathione and N-acetyl-S-butylcysteinyl-glycine ethyl ester.


1988 ◽  
Vol 53 (11) ◽  
pp. 2810-2824 ◽  
Author(s):  
Ilmars Sekacis ◽  
Mark Shenderovich ◽  
Gregory Nikiforovich ◽  
Edvards Liepinš ◽  
Ludmila Polevaya ◽  
...  

A group of synthetic peptides including Boc-Lys-Phe-X-Y, X = Ala (I, III) or Thr (II), Y = Pro (I, II) or Ala (III) was studied by means of 1H NMR spectroscopy and theoretical conformational analysis. Compound I in DMSO shows two conformers with the trans- and cis-configuration of the peptide bond Ala-Pro. The salt bridge between the Lys ε-amino group and the C-terminal carboxyl is featured by magnetic nonequivalence of the Lys CεH2 protons. The space structure of I and II was found to possess a salt bridge fixed by an unusual turn in the chain formed by the Lys side chain and the C-terminal dipeptide with the trans-peptide bond X-Pro. Since a stable ionic bond in III and in the cis-conformer of I has not been observed, its contribution to stabilization of the space structure of the peptides in DMSO appears rather small.


2012 ◽  
Vol 14 (8) ◽  
pp. 2162-2163 ◽  
Author(s):  
Bill Morandi ◽  
Amund Dolva ◽  
E. M. Carreira

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