Boyd D B, Hermann R B, Presti D E, Marsh M M
J Med Chem. 1975 Apr;18(4):408-17. doi: 10.1021/jm00238a018.
Molecular orbital calculations by the CNDO/2 method are used to study the molecular and electronic details involved in the initial phases of the opening of the beta-lactam ring of a model cephalosporin structure, 7-amino-3-acetoxymethyl-3-cephem. The effect of a simple nucleophile, OH-, approaching the carbonyl carbon center of the beta-lactam ring is monitored by following the charge redistributions that occur in the bicyclic system and in the 3 side chain. A migration of electron density to the ester oxygen of the CH2OAc group is observed with concomitant weakening of the CH2-OAc bond. The results are discussed in relation to the mechanism of acylation of bacterial cell wall enzymes by beta-lactam antibiotics and in relation to the hydrolysis of these molecules. The results indicate that the ability of the 3' substituent of cephalosporins to stabilize electron density transferred to it, i.e., the leavability of the 3' moiety, can be an important factor in activating the beta-lactam toward nucleophilic attack.
采用CNDO/2方法进行分子轨道计算，以研究模型头孢菌素结构7-氨基-3-乙酰氧甲基-3-头孢烯β-内酰胺环开环初始阶段所涉及的分子和电子细节。通过跟踪双环系统和3-侧链中发生的电荷重新分布，监测简单亲核试剂OH-接近β-内酰胺环羰基碳中心的影响。观察到电子密度向CH2OAc基团的酯氧迁移，同时CH2-OAc键减弱。结合β-内酰胺抗生素对细菌细胞壁酶的酰化机制以及这些分子的水解对结果进行了讨论。结果表明，头孢菌素3'-取代基稳定转移至其上的电子密度的能力，即3'-部分的离去能力，可能是激活β-内酰胺以进行亲核攻击的一个重要因素。
