A structural study of N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6-di(aziridin-1-yl)-1,3,5-triazin-2-amine by density functional theory calculations

Timoshchuk K.V., Chernov I.S., Shemchuk O.S., Protas A.V., Mikolaichuk O.V., Popova E.A., Molchanov O.E., Maistrenko D.N. A structural study of N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6-di(aziridin-1-yl)-1,3,5- triazin-2-amine by density functional theory calculations. Scientific and Technical Journal of Information Technologies, Mechanics and Optics, 2025, vol. 25, no. 4, pp. 643–650. doi: 10.17586/2226-1494-2025-25-4-643-650

Currently, antitumor drug therapy is represented by three directions: chemotherapy, targeted therapy and immunotherapy. Chemotherapy is a non-specific treatment that uses chemicals that inhibit cell proliferation, affect cellular DNA or RNA and cellular metabolism which contributes to the destruction of all dividing cells. Six-membered heterocyclic ring — 1,3,5-triazine and its derivatives are increasingly found in the literature as DNA alkylating agents. One of such triazine derivatives, N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6-di(aziridin-1-yl)-1,3,5-triazin-2-amine, previously obtained in our research group, was characterized, and its structure was optimized using the Density Functional Theory (DFT) method, B3LYP functional and 6-31G basis set. The theoretically obtained spectral characteristics were confirmed by practical results with a high degree of convergence. In this work, quantum chemical calculations were performed at different DFT levels using the ORCA software package. The structure of N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6- di(aziridin-1-yl)-1,3,5-triazin-2-amine was optimized using the B3LYP functional with the 6-31G basis set. ¹H and ¹³C (DMSO-d₆) Nuclear Magnetic Resonance spectra were recorded on a Bruker 300 Avance instrument at frequencies of 400.0 and 100.0 MHz, respectively. At the first stage of computer modeling, the electronic structure of the molecule was calculated using the DFT method and the geometry was optimized. The calculation was performed in the 6-31G basis set with the B3LYP functional and taking into account the polarization of the solvent (water) with a relative permittivity of 78.54. The charges on the atoms were estimated using the Mulliken scheme. The energy values (eV) for the molecule are: HOMO: –6.279, LUMO: –1.147. The optimized structure was stable, and the charge distribution on the atoms allows us to conclude that there are three possible conformations of N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6- di(aziridin-1-yl)-1,3,5-triazin-2-amine. In the next step, for calculations with periodic boundary conditions, 20 studied molecules and approximately 1.3·10⁵ water molecules were placed in a cubic box with sides of 16 nm; the distance between N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6-di(aziridin-1-yl)-1,3,5-triazin-2-amine molecules was at least 3 nm, and the distance from the molecule to the wall was at least 1.5 nm. The force field for the OPLS-AA/M system was used; the simulation time was 200 ns with a step of 1 fs. Then, in the GROMACS 2023 package in the NVT ensemble with a Berendsen thermostat and a barostat for 400 ps with a time step of 0.1 fs under the condition at temperature T = 298.15 K and pressure P = 100 kPa, solvation of the system, energy minimization and equilibration were carried out. It is shown that when performing the dynamics of association, these molecules do not form aggregates in an aqueous solution. In this work, the synthesis and characterization of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-4,6-di(aziridin- 1-yl)-1,3,5-triazin-2-amine by spectroscopic methods are described. The results of the molecular docking studies are consistent with the in vitro antitumor activity which showed that the compound exhibits maximum efficiency and show approximate binding energies in the range from –1.034 to –4.578 kcal·mol^–1 N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethyl)- 4,6-di(aziridin-1-yl)-1,3,5-triazin-2-amine has been demonstrated to have a high affinity for serum albumin, indicating its potential for serum distribution.

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