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<p>5-Azacytidine (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1&#xa0;H)-one) is a triazine analogue of cytidine utilized in chemotherapy for myelogenous leukemia, myelodysplastic syndromes, acute myeloid leukemia, and bone marrow disorders. Its therapeutic action is attributed to DNA methyltransferase inhibition via hypomethylation. Despite the known existence of eight reported crystalline polymorphs, no crystal structures have been elucidated to date. This work presents the first single-crystal X-ray diffraction structure of the anhydrous triclinic polymorph (Form I) of 5-azacytidine, alongside methods for obtaining phase-pure crystals. The crystal packing is characterized by R<sup>2</sup><sub>2</sub>(8) hydrogen-bonding motifs and homosynthons. Quantum chemical calculations (DLPNO-CCSD(T)/cc-pVTZ) reveal that the hydrogen bonds responsible for the R<sup>2</sup><sub>2</sub>(8) homosynthons exhibit an energy of − 59.07&#xa0;kJ/mol. The lattice energy was calculated using both molecular associate (200.7&#xa0;kJ/mol) and periodic approximation (170&#xa0;kJ/mol at PBE/800&#xa0;eV) methods. NMR DOSY studies indicate the presence of dynamic dimeric or oligomeric species in solution, undergoing fast exchange via intermolecular hydrogen bonds involving both ribose and heterocyclic moieties. Thermodynamic parameters derived from experimental solubility data (in cyclohexane) yield a sublimation enthalpy and corresponding free energy at 298 K of 122.0 and 66.4&#xa0;kJ/mol, respectively. The calculated entropy of fusion ΔS<sup>298</sup> is 108.67&#xa0;J/mol/K, corresponding to TΔS<sup>298</sup> value of 32.38&#xa0;kJ/mol. Comprehensive physicochemical characterization includes thermal analysis (TGA, DSC), solubility studies, and a topological analysis of the hydrogen-bonding network according to Etter’s formalism.</p>

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The structure and lattice energy of 5-azacytidine. An insight on computational studies and thermodynamic properties

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Elizaveta E. Posypayko,
  • Alexander R. Romanenko,
  • Alexander Yu. Rudenko,
  • Andrey K. Ratnikov,
  • Alexander A. Korlyukov

摘要

5-Azacytidine (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1 H)-one) is a triazine analogue of cytidine utilized in chemotherapy for myelogenous leukemia, myelodysplastic syndromes, acute myeloid leukemia, and bone marrow disorders. Its therapeutic action is attributed to DNA methyltransferase inhibition via hypomethylation. Despite the known existence of eight reported crystalline polymorphs, no crystal structures have been elucidated to date. This work presents the first single-crystal X-ray diffraction structure of the anhydrous triclinic polymorph (Form I) of 5-azacytidine, alongside methods for obtaining phase-pure crystals. The crystal packing is characterized by R22(8) hydrogen-bonding motifs and homosynthons. Quantum chemical calculations (DLPNO-CCSD(T)/cc-pVTZ) reveal that the hydrogen bonds responsible for the R22(8) homosynthons exhibit an energy of − 59.07 kJ/mol. The lattice energy was calculated using both molecular associate (200.7 kJ/mol) and periodic approximation (170 kJ/mol at PBE/800 eV) methods. NMR DOSY studies indicate the presence of dynamic dimeric or oligomeric species in solution, undergoing fast exchange via intermolecular hydrogen bonds involving both ribose and heterocyclic moieties. Thermodynamic parameters derived from experimental solubility data (in cyclohexane) yield a sublimation enthalpy and corresponding free energy at 298 K of 122.0 and 66.4 kJ/mol, respectively. The calculated entropy of fusion ΔS298 is 108.67 J/mol/K, corresponding to TΔS298 value of 32.38 kJ/mol. Comprehensive physicochemical characterization includes thermal analysis (TGA, DSC), solubility studies, and a topological analysis of the hydrogen-bonding network according to Etter’s formalism.