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Synthesis and biological activity of N-phosphonacetyl-L-aspartate’s structural analogs N-(α-dietoxyphosphorylcyclopropylcarbonyl)-amino acids

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Abstract

Objectives. With the development and improvement of new delivery systems for substances of various natures, organophosphorus compounds with an antimetabolic mechanism of action have become 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 of which are bio-rationally developed analogs of the transition state of carbamoylaspartate in the biosynthesis of pyrimidine bases, which is catalyzed by the enzyme aspartate transcarbamoylase (ATCase). Despite their high activity, these compounds have not found widespread use as anticancer agents due to a large number of side-effects and low bioavailability. Given the emerging opportunities for the delivery of phosphate and phosphonate derivatives into target cells, obtaining more effective analogs of PALA seems to be an interesting and promising research objective. The goal of the present study was thus to synthesize and study the biological activities of novel PALA analogs that are derivatives of phosphonacetic acid.

Methods. For directed work within the framework of the study, we used the molecular docking method, which allowed us to simulate the binding of N-(α-diethoxyphosphorylcyclopropylcarbonyl)- substituted amino acids to ATCase. The target compounds were synthesized using classical methods of organic synthesis. The obtained compounds’ cytotoxicity was probed in relation to cell lines 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)-substituted amino acids was carried out. A few of the synthesized derivatives were tested for anticancer activity, but none displayed significant cytotoxicity.

Conclusions. N-(α-diethoxyphosphorylcyclopropylcarbonyl)-substituted amino acids are synthetically available analogs of PALA, a compound capable of strong interaction with ATCase. However, the compounds 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 the phosphonate building block.

About the Authors

I. S. Kuzmin
D.I. Mendeleev University of Chemical Technology of Russia
Russian Federation

Ivan S. Kuzmin, Leading Engineer, Department of Chemistry and Technology of Biomedical Drugs

9, Miusskaya pl., Moscow , 125047, Russia



G. A. Toporkov
D.I. Mendeleev University of Chemical Technology of Russia
Russian Federation

Grigorii A. Toporkov, Master Student Department of Chemistry and Technology of Biomedical Drugs

9, Miusskaya pl., Moscow , 125047, Russia



D. Yu. Yuriev
D.I. Mendeleev University of Chemical Technology of Russia
Russian Federation

Danil Yu. Yuriev, Master Student, Department of Chemistry and Technology of Biomedical Drugs

9, Miusskaya pl., Moscow , 125047, Russia



A. V. Kalistratova
D.I. Mendeleev University of Chemical Technology of Russia
Russian Federation

Antonida V. Kalistratova, Cand. of Sci. (Chemistry), Assistant Professor, Department of Chemistry and Technology of Biomedical Drugs. ResearcherID B-4401-2018

9, Miusskaya pl., Moscow , 125047, Russia



L. V. Kovalenko
D.I. Mendeleev University of Chemical Technology of Russia
Russian Federation

Leonid V. Kovalenko, Dr. of Sci. (Chemistry), Professor, Head of the Department of Chemistry and Technology of Biomedical Drugs

9, Miusskaya pl., Moscow , 125047, Russia



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Supplementary files

1. Fig. 3a. An N-phosphonacetyl-L-aspartate molecule in the active site of aspartate transcarbomoylase (X-ray diffraction data; image obtained using the Chimera software).
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2. Fig. 3b. An N-(α-dihydroxyphosphorylcyclopropylcarbonyl) aspartic acid molecule in the active site of aspartate transcarbomoylase (conformation modeled with Autodock; image obtained with the Chimera software).
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3. This is to certify that the paper titled Synthesis and biological activity of N-phosphonacetyl-L-aspartate’s structural analogs N-(α-dietoxyphosphorylcyclopropylcarbonyl)amino acids commissioned to us by Ivan S. Kuzmin, Danil Yu. Yuriev, Grigorii A. Toporkov, Antonida V. Kalistratova, Leonid V. Kovalenko has been edited for English language and spelling by Enago, an editing brand of Crimson Interactive Inc..
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  • The authors synthesized novel PALA analogs that were derivatives of phosphonacetic acid and studied their biological activities.
  • The obtained compounds’ cytotoxicity was probed in relation to cell lines of human breast cancer (MDA-MB-231), skin cancer (A-375), and glioblastoma (U-87 MG).
  • The compounds 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 the phosphonate building block.

For citation:


Kuzmin I.S., Toporkov G.A., Yuriev D.Yu., Kalistratova A.V., Kovalenko L.V. Synthesis and biological activity of N-phosphonacetyl-L-aspartate’s structural analogs N-(α-dietoxyphosphorylcyclopropylcarbonyl)-amino acids. Fine Chemical Technologies. 2020;15(5):26-35.

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ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)