Organic Chemistry: Current Research
Open Access
ISSN: 2161-0401
ISSN: 2161-0401
Istvan Koteles and Sandor Hosztafi
Semmelweis University, Hungary
Posters & Accepted Abstracts: Organic Chem Curr Res
Drugs of abuse are small molecules that typically do not induce an antibody response following injection or inhalation. To induce antibodies against small molecules, structural surrogates of the molecules, which were named “haptens”, must be coupled to immunogenic proteins, called “carriers”. These structural surrogates are typically drug-linker adducts, in which the linker has a terminal functional group 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. We have designed two methods for the synthesis of these haptens: At the start of our experiments 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 unaccomplishable. As an alternative route the normorphine-compounds were reacted with N-chloroacetyl glycine ethyl ester. After column chromatography purification the structures of the new compounds were elucidated by NMR and mass spectroscopy. N-Alkylation of 4, 5-epoxy-normorphinans was achieved by the reaction with alkyl bromides which contain a protected amino group. In our research project we used N-(2-bromoethyl)-phthalimide and N-(3-bromopropyl)- phthalimide in dimethylformamide to N-alkylate the normorphine derivatives, in the presence of sodium hydrogen carbonate. After column chromatography purification boiling with hydrazine in ethanol the protecting group can be removed, and the results are N-beta-amino ethyl and N-gamma-aminopropyl-nor compounds. The structures were elucidated by NMR and mass spectroscopy as previously. At the current state of research we are going to send the samples for biological and animal experiments to screen opioid activity.
Recent Publications
1. Matyas G, et al. (2014) Facial recognition of heroin vaccine opiates: type 1 cross-reactivities of antibodies induced by hydrolytically stable haptenic surrogates of heroin, 6-acetylmorphine, and morphine. Vaccine 32(13):1473-1479.
2. Sulima A, et al. (2018) A stable heroin analogue that can serve as a vaccine hapten to induce antibodies that block the effects of heroin and its metabolites in rodents and that cross-react immunologically with related drugs of abuse. Journal of Medicinal Chemistry 61(1):329-343.
3. Alving C R, et al. (2014) Adjuvants for vaccines to drugs of abuse and addiction. Vaccine 32(42):5382-5389.
4. Torres O B, et al. (2014) Characterization and optimization of heroin hapten-BSA conjugates: method development for the synthesis of reproducible hapten-based vaccines. Analytical and Bioanalytical Chemistry 406(24):5927-5937.
5. Li F, et al (2014) Synthesis and immunological effects of heroin vaccines. Organic & Biomolecular Chemistry 12(37):7211-7232.
Istvan Koteles has obtained his Graduation at the Semmelweis University in the Faculty of Pharmacy in 2015. He has participated at the Student’s Scientific Conference for three years and has achieved 3rd place twice and 1st place once with the topic “Synthesis of morphine hapten derivatives” supervised by Sandor Hosztafi a Senior Research Fellow. He is pursuing his PhD at the Institute of Pharmaceutical Chemistry and working as an Instructor of the Hungarian and English laboratory practices for the graduate level students.