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Synthesis and biological activity of N-phosphonacetyl-L-aspartate’s structural analogs N-(α-dietoxyphosphorylcyclopropylcarbonyl)-amino acidsстатья
- Авторы: Kuzmin I.S., Toporkov G.A., Yuriev D.Yu, Kalistratova A.V., Kovalenko L.V.
- Журнал: Fine Chemical Technologies
- Том: 15
- Номер: 5
- Год издания: 2020
- Первая страница: 26
- Последняя страница: 35
- DOI: 10.32362/2410-6593-2020-15-5-26-35
- Аннотация: Objectives. With the development and improvement of new delivery systems for substances ofvarious natures, organophosphorus compounds with an antimetabolic mechanism of action havebecome relevant again. A few examples of them are organophosphorus analogs of carboxylic acids,such as N-phosphonacetyl-L-aspartate (PALA) and N-phosphonacetyl-L-isoasparagine, both ofwhich are bio-rationally developed analogs of the transition state of carbamoylaspartate in thebiosynthesis of pyrimidine bases, which is catalyzed by the enzyme aspartate transcarbamoylase(ATCase). Despite their high activity, these compounds have not found widespread use asanticancer agents due to a large number of side-effects and low bioavailability. Given theemerging opportunities for the delivery of phosphate and phosphonate derivatives into targetcells, obtaining more effective analogs of PALA seems to be an interesting and promising researchobjective. The goal of the present study was thus to synthesize and study the biological activitiesof novel PALA analogs that are derivatives of phosphonacetic acid.Methods. For directed work within the framework of the study, we used the molecular dockingmethod, which allowed us to simulate the binding of N-(α-diethoxyphosphorylcyclopropylcarbonyl)-substituted amino acids to ATCase. The target compounds were synthesized using classicalmethods of organic synthesis. The obtained compounds’ cytotoxicity was probed in relation to celllines of human breast cancer (MDA-MB-231), skin cancer (A-375), and glioblastoma (U-87 MG).Results. The synthesis of eight novel N-(α-diethoxyphosphorylcyclopropylcarbonyl)-substitutedamino acids was carried out. A few of the synthesized derivatives were tested for anticanceractivity, but none displayed significant cytotoxicity.Conclusions. N-(α-diethoxyphosphorylcyclopropylcarbonyl)-substituted amino acids are syntheticallyavailable analogs of PALA, a compound capable of strong interaction with ATCase. However, thecompounds synthesized in this work did not display any pronounced anticancer properties.One of the reasons for the observed low activity may be the presence of ether groups in thephosphonate building block.Keywords: phosphonocarboxylic acids, N-phosphonacetyl-L-aspartate (PALA), aspartatetranscarbamylase (ATCase), α-diethoxyphosphonacetic acid, α-diethoxyphosphorylcyclopropylcarboxylic acid, N-(α-diethoxyphosphorylcyclopropylcarbonyl)amino acids.
- Добавил в систему: Калистратова Антонида Владимировна