Quantum Chemical\nStudies of Bendamustine and Melphalan\nin Water as Antiblood Cancer Agents

A hybrid B3LYP version\nof the Density Functional Theory\nwas applied\nin full geometry optimization followed by vibrational analysis of\nmustard-type molecules acting as antiblood cancer agents: melphalan\nand bendamustine. All calculations were performed with water as a\nsolvent. In addition to the ground-state properties (dipole moment,\nquadrupole moment, dipole polarizability, solvated surface and volume,\nzero-point vibration energy, total entropic term), properties that\ncharacterize adiabatic redox processes (ionization energy, electron\naffinity, molecular electronegativity, chemical hardness, electrophilicity\nindex) together with the absolute oxidation and reduction potentials\nwere evaluated. Vibrational frequencies were also calculated, and\nfrontier orbitals were displayed and analyzed. Bendamustine and melphalan\nin their canonical (amino acid, A) forms were found to have very low\nionization energies <i>E</i><sub>i</sub> = 4.85 eV and consequently\nlow (in absolute value) oxidation potentials <i>E</i><sub>ox</sub><sup>o̷</sup> = −4.92 V based on the reaction\nGibbs energies; this indicates considerable antioxidant capacity.\nThe zwitterionic (Z) form of melphalan is more stable in water as\nopposite the bendamustine, for which the Z-form is less stable in\nwater: Δ<i>G</i><sub>Z‑A</sub> = −2.7\nand 2.9 kcal mol<sup>–1</sup>, respectively. The cationic residues\nof bendamustine-hydrochloride (bendamustinium) and melphalan-hydrochloride\n(melphalanium) have properties essentially analogous to those of the\ncanonical forms, except for a very large dipole moment for the Bd-Z, <i>p</i> = 29.7 debye. All calculations were refined with the ab\ninitio post-Hartree–Fock method DLPNO–CCSD(T), which\nis a variant of the “gold standard coupled cluster theory”\nCCSD(T) that accounts for the major part of the correlation energy\n(DLPNO–CCSD(T)–Domain Localized Pair Natural Orbitals–Coupled\nCluster Singles + Doubles + Triples method). It is confirmed that\n(i) the canonical form of bendamustine is more stable in water compared\nto the zwitterionic form by Δ<i>G</i><sub>Z‑A</sub> = 4.8 kcal mol<sup>–1</sup>; (ii) low ionization energy <i>E</i><sub>i</sub> = 5.10 eV causes low absolute oxidation potential <i>E</i><sub>ox</sub>* = −5.10 V and increased antioxidant\ncapacity; and (iii) the redox properties of bendamustinium are analogous\nto the zwitterionic form of bendamustine and are significantly different\nfrom the canonical form of bendamustine. The energy profile of electron–proton\ncoupled transfer shows that the SET-PT mechanism proceeds over lower\nbarriers than the concurrent SPLET mechanism.