Hill G C, Wunz T P, MacKenzie N E, Gooley P R, Remers W A
Department of Pharmaceutical Sciences, College of Pharmacy University of Arizona, Tucson 85721.
J Med Chem. 1991 Jul;34(7):2079-88. doi: 10.1021/jm00111a024.
Cyanocycline A was found to have a pKa of 6.6. Protonation of N14 was established by 1H NMR spectroscopy. In strongly acidic solution the oxazolidine ring opened irreversibly. A model was derived for the binding of naphthyridinomycin and cyanocycline A to the hexanucleotide duplex d(ATGCAT)2, by using the molecular mechanics and dynamics modules of AMBER 3.0. It involved protonation on the oxazolidine-ring nitrogen, reduction of the quinone ring to a hydroquinone, formation of an iminium ion with loss of the C7 substituent, noncovalent binding in the minor groove with the hydroquinone ring in the 3'-direction from guanine, and covalent binding to the 2-amino group of this guanine with C7 adopting the R configuration. This model is consistent with the experimental evidence on the DNA binding of these drugs. An alternative binding mode based on opening of the oxazolidine ring and alkylation at C3a also was feasible according to molecular mechanics calculations. The geometry of naphthyridinomycin does not permit interstrand cross-linking involving both C3a and C7, but formation of a cross-link to protein appears possible. When the covalent naphthyridinomycin-d(ATGCAT)2 models were refined in the presence of water and counterions, the models with the most favorable net binding enthalpies were the same as those produced by simulation in vacuum. Qualitative estimates of the relative entropy changes resulting from adduct formation were based on the number of ordered (hydrogen bonded) water molecules released from d(ATGCAT)2 and from the drug. In all cases but one, d(ATGCAT)2 loses five water molecules. It loses six in the C3a covalent model with 5',S geometry. Naphthyridinomycin hydroquinone loses up to two water molecules, depending on the particular adduct. The 3',R model was again favored for the C7 covalent adduct. Among the C3a covalent models, the one with 5',R geometry lost the second most water molecules, but it had the best binding enthalpy.
发现氰基环素A的pKa为6.6。通过1H NMR光谱确定了N14的质子化。在强酸性溶液中，恶唑烷环不可逆地打开。利用AMBER 3.0的分子力学和动力学模块，推导了萘啶霉素和氰基环素A与六核苷酸双链体d(ATGCAT)2结合的模型。它包括恶唑烷环氮的质子化、醌环还原为对苯二酚、形成亚胺离子并失去C7取代基、在小沟中与对苯二酚环非共价结合（在鸟嘌呤的3'方向）以及与该鸟嘌呤的2-氨基共价结合且C7采用R构型。该模型与这些药物与DNA结合的实验证据一致。根据分子力学计算，基于恶唑烷环打开和C3a烷基化的另一种结合模式也是可行的。萘啶霉素的几何结构不允许涉及C3a和C7的链间交联，但与蛋白质形成交联似乎是可能的。当在水和抗衡离子存在下对共价萘啶霉素-d(ATGCAT)2模型进行优化时，具有最有利净结合焓的模型与在真空中模拟产生的模型相同。由加合物形成导致的相对熵变化的定性估计基于从d(ATGCAT)2和药物中释放的有序（氢键结合）水分子的数量。在所有情况中，除了一种情况外，d(ATGCAT)2失去五个水分子。在具有5',S几何结构的C3a共价模型中它失去六个水分子。萘啶霉素对苯二酚最多失去两个水分子，这取决于特定的加合物。对于C7共价加合物，3',R模型再次受到青睐。在C3a共价模型中，具有5',R几何结构的模型失去的水分子数量居第二，但它具有最佳的结合焓。
