Guddneppanavar Rajsekhar, Bierbach Ulrich
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.
Anticancer Agents Med Chem. 2007 Jan;7(1):125-38. doi: 10.2174/187152007779313991.
The minor-groove is an important receptor for enzymes and proteins involved in the processing and expression of genomic DNA. Small molecules capable of interfering with these processes by virtue of their ability to form adducts within the recognition sequences targeted by these enzymes/proteins have potential applications as cytotoxic and gene-regulating agents. Until recently, the targeting of the minor groove by platinum-based agents has been a widely unexplored opportunity. As part of this focused review on irreversible minor-groove modifying agents acting on adenine-N3, we summarize work performed in our laboratory and by our collaborators on a novel platinum-acridine conjugate, PT-ACRAMTU (PtCl(en)(ACRAMTU)(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, acridinium cation). The design of this agent as a non-cisplatin type pharmacophore has led to a groundbreaking discovery, the unprecedented intercalator-driven formation of platinum-adenine-N3 adducts in the minor groove of DNA. The minor-groove reactivity of PT-ACRAMTU represents a new paradigm in platinum-DNA interactions, which opens new avenues in the design of platinum-based therapeutics acting by a mechanism different from that of agents currently in clinical use.
小沟是参与基因组DNA加工和表达的酶及蛋白质的重要受体。能够凭借在这些酶/蛋白质靶向的识别序列内形成加合物来干扰这些过程的小分子，作为细胞毒性和基因调节剂具有潜在应用价值。直到最近，基于铂的试剂靶向小沟仍是一个未被广泛探索的机会。作为对作用于腺嘌呤-N3的不可逆小沟修饰剂的这篇重点综述的一部分，我们总结了我们实验室以及我们的合作者对一种新型铂-吖啶共轭物PT-ACRAMTU（PtCl(en)(ACRAMTU)(2)，en = 乙二胺，ACRAMTU = 1-[2-(吖啶-9-基氨基)乙基]-1,3-二甲基硫脲，吖啶鎓阳离子）所开展的工作。将该试剂设计为非顺铂型药效基团带来了一项开创性发现，即在DNA小沟中前所未有的由嵌入剂驱动形成铂-腺嘌呤-N3加合物。PT-ACRAMTU的小沟反应性代表了铂-DNA相互作用的一种新范式，这为设计作用机制不同于目前临床使用试剂的铂类治疗药物开辟了新途径。
