Boča Roman, Štofko Juraj, Ladická Miriam, Rajnák Cyril
Faculty of Health Science, University of Ss. Cyril and Methodius, Trnava 91701, Slovakia.
National Cancer Institute, Bratislava 83310, Slovakia.
ACS Omega. 2025 May 16;10(21):21581-21588. doi: 10.1021/acsomega.5c00740. eCollection 2025 Jun 3.
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.
使用量子化学计算方法研究了三种氮芥类抗血癌药物，即环磷酰胺、尿嘧啶氮芥和苯丁酸氮芥。第一种是近似的B3LYP方法，适用于中小分子的分子几何结构快速优化和振动分析。它提供基态性质（偶极矩和极化率、四极矩、溶剂化体积和表面积、零点振动能量、熵贡献和NMR屏蔽常数）以及全局氧化还原绝热性质（电子亲和能、电离能、化学硬度、分子电负性、亲电性指数、绝对还原电位和氧化电位）。计算是在针对水进行参数化的溶剂中进行的。通过使用DLPNO-CCSD-(T) - 域定域对自然轨道耦合簇单重态 + 双重态 + 三重态方法改进了计算。这种后哈特里 - 福克方法几乎考虑了全部电子相关能。将计算得到的分子描述符与美法仑和苯达莫司汀在其标准形式和两性离子形式下得到的描述符进行了比较。发现整体分子性质（偶极极化率、四极矩、溶剂化体积和表面积、零点振动能量和总熵项）与分子摩尔质量相关。尿嘧啶氮芥（120）和苯丁酸氮芥（116）的电离能与美法仑（117）和苯达莫司汀（112、124）计算得到的电离能相近；所有数据单位为kcal mol。与苯达莫司汀（-4.9 / -5.1 V）相比，环磷酰胺（141）增加的电离能导致最负的绝对氧化电位（-6.1 / -6.6 V）；斜杠分隔了通过B3LYP和DLPNO-CCSD-(T)方法获得的数据。苯丁酸氮芥（酸）的两步电子 - 质子耦合转移跨越相同的能垒，但顺序相反，因此“单电子转移后质子转移”（SET-PT）和“顺序质子损失电子转移”（SPLET）机制同样可能。
