Carbocyclic Nucleoside Isosteres as Potential Antitumor

该项目的主要目标是系统地探测核苷/核苷酸结合酶与构象刚性底物的组合，以了解它们的首选结合模式。这是通过在双环[3.1.0]己烷模板上构建碳环核苷类似物来实现的，该模板通过将糖的构象锁定在两种首选的自然构象之一（北或南）来消除糖部分固有的灵活性。该项目的第二个目标是构建含有许多锁定核苷酸单元的修饰核酸，分别加强或破坏与南构象和北构象相关的典型B-或A- dna构象。主要研究结果如下：

The main objective of this project has been the systematic probing of nucleoside/nucleotide binding enzymes with sets of conformationally rigid substrates to learn about their preferred binding mode. This has been accomplished by constructing carbocyclic nucleoside analogues on a bicyclo[3.1.0]hexane template which essentially removes the inherent flexibility of the sugar moiety by locking the conformation of the sugar in one of the two preferred natural conformations (North or South). A secondary objective of this project has been the construction of modified nucleic acids that incorporate a number of locked nucleotide units to either reinforce or disrupt the typical B- or A-DNA conformations associated with South and North conformations, respectively. The major findings are: 1) The corresponding 5'-triphosphates of the locked antipodes of adenosine (N-MCdA and S-MCdA) showed that that the most effective HIV RT inhibitor (N-MCdA-5'-triphosphate) inhibited DNA elongation beyond the polymerase site and showed great effectiveness against all HIV-resistant strains that function by the excision mechanism. This approach offers a novel and promising way to overcome HIV resistance. 2) A series of short oligodeoxynucleotides (ODNs) corrresponding to the self-complementary EcoR1 recognition sequence [ds(5'-CGCGAATTCGCG-3')] where the middle A's and the middle T's have been replaced by locked adenosines and locked thymidines have been synthesized and the structures solved by NMR, CD and calorimetry. The results will be published shortly. 3) A novel synthesis developed for North conformers involving a lipase-catalyzed resolution step of the bicyclo[3.1.0]hexane system was very successful and reproducible in a preparative scale by a contractor. Supplies of all building blocks for additional DNA syntheses will be forthcoming.