Quantum Chemical Studies of Anti-Blood Cancer Agents, II.

Three anti-blood cancer agents of the nitrogen mustard type, namely, cyclophosphamide, uramustine, and chlorambucil, were studied using quantum chemical computational methods. The first, approximate B3LYP method is suitable for rapid optimization of molecular geometry and vibrational analysis of small- or medium-sized molecules. It provides ground-state properties (dipole moment and polarizability, quadrupole moment, solvated volume and surface area, energy of zero-point vibration, entropic contribution, and NMR shielding constants) and global redox adiabatic properties (electron affinity, ionization energy, chemical hardness, molecular electronegativity, electrophilicity index, absolute reduction, and oxidation potentials). Calculations were performed in a solvent parametrized for water. The calculations were improved by using the DLPNO-CCSD-(T) - domain localized pair natural orbitals-coupled cluster singles + doubles + triples method. This post-Hartree-Fock method accounts for almost the full electron correlation energy. The calculated molecular descriptors were compared to those obtained for melphalan and bendamustine in their canonical and zwitterionic forms. Bulk molecular properties (dipole polarizability, quadrupole moment, solvated volume and surface area, zero-point vibration energy, and total entropic term) were found to correlate with molecular molar mass. The ionization energies of uramustine (120) and chlorambucil (116) are close to those calculated for melphalan (117) and bendamustine (112, 124); all data in kcal mol. The increased ionization energy for cyclophosphamide (141) causes the most negative absolute oxidation potential (-6.1/-6.6 V) compared to bendamustine (-4.9/-5.1 V); the slash separates data obtained by the B3LYP and DLPNO-CCSD-(T) methods. The two-step electron-proton coupled transfer for chlorambucil (acid) occurs across the same energy barrier, but in the opposite order, so that "single electron transfer followed by proton transfer" (SET-PT) and "sequential proton loss electron transfer" (SPLET) mechanisms are equally probable.