Lombardy R L, Tanious F A, Ramachandran K, Tidwell R R, Wilson W D
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
J Med Chem. 1996 Mar 29;39(7):1452-62. doi: 10.1021/jm9507946.
Considerable evidence now indicates that DNA is the receptor site for dicationic benzimidazole anti-opportunistic infections agents (Bell, C.A.; Dykstra, C.C.; Naiman N.A.I.; Cory, M.; Fairley, T.A.; Tidwell, R.R. Antimicrob. Agents Chemother. 1993, 37, 2668-2673. Tidwell R.R.; Jones, S.K.; Naiman, N.A.; Berger, I.C.; Brake, W.R.; Dykstra, C.C.; Hall, J.E. Antimicrob. Agents Chemother. 1993, 37, 1713-1716). To obtain additional information on benzimidazole-receptor complexes, the syntheses and DNA interactions of series of symmetric benzimidazole cations, linked by alkyl or alkenyl groups, have been evaluated. Biophysical techniques, thermal denaturation measurement (deltaTm), kinetics, and circular dichroism (CD) have been used in conjunction with NMR and molecular modeling to evaluate the affinities, binding mode, and structure of complexes formed between these compounds and DNA. All the compounds bind strongly to DNA samples with four or more consecutive AT base pairs, and they bind negligibly to GC rich DNA or to RNA. Spectral and kinetics characteristics of the benzimidazole complexes indicate that the compounds bind in the DNA minor groove at AT sequences. NMR and molecular modeling of the complex formed between an ethylene-linked benzimidazole derivative, 5, and the self-complementary oligomer d(GCGAATTCGC) have been used to establish structural details for the minor groove complex. These results have been used as a starting point for molecular mechanics calculations to refine the model of the minor groove-benzimidazole complex and to draw conclusions regarding the molecular basis for the effects of substituent changes on benzimidazole-DNA affinities.
目前大量证据表明，DNA是双阳离子苯并咪唑抗机会性感染药物的受体位点（贝尔，C.A.；戴克斯特拉，C.C.；奈曼，N.A.I.；科里，M.；费尔利，T.A.；蒂德韦尔，R.R.《抗菌剂与化疗》，1993年，37卷，2668 - 2673页。蒂德韦尔，R.R.；琼斯，S.K.；奈曼，N.A.；伯杰，I.C.；布雷克，W.R.；戴克斯特拉，C.C.；霍尔，J.E.《抗菌剂与化疗》，1993年，37卷，1713 - 1716页）。为了获取有关苯并咪唑 - 受体复合物的更多信息，已对一系列通过烷基或烯基连接的对称苯并咪唑阳离子的合成及其与DNA的相互作用进行了评估。生物物理技术、热变性测量（ΔTm）、动力学和圆二色性（CD）已与核磁共振（NMR）和分子建模结合使用，以评估这些化合物与DNA形成的复合物的亲和力、结合模式和结构。所有这些化合物都能与具有四个或更多连续AT碱基对的DNA样品强烈结合，而与富含GC的DNA或RNA的结合可以忽略不计。苯并咪唑复合物的光谱和动力学特征表明，这些化合物在DNA小沟中的AT序列处结合。已利用乙烯连接的苯并咪唑衍生物5与自互补寡聚物d(GCGAATTCGC)形成的复合物的核磁共振和分子建模来确定小沟复合物的结构细节。这些结果已被用作分子力学计算的起点，以完善小沟 - 苯并咪唑复合物的模型，并就取代基变化对苯并咪唑 - DNA亲和力影响的分子基础得出结论。
