Carbocyclic Nucleoside Isosteres as Potential Antitumor

我的实验室继续研究双环[3.1.0]己烷模板作为构建新型构象锁定碳环核苷的平台。我们使用这些修饰的核苷的目的是(1)确定参与核苷、核苷酸和寡核苷酸生物化学的酶的构象偏好；以及(2)根据我们对其生化作用机制的了解，开发可能的抗肿瘤/抗病毒药物。这一知识的应用已成功地应用于设计和合成针对精确治疗靶点的核苷类似物，如卡波西肉瘤病毒、艾滋病毒、疱疹病毒和最近的痘病毒。化学合成的N-甲基卡巴核苷5‘-三磷酸作为HIV逆转录酶延迟链终止物的作用以及它们克服HIV耐药性的切除机制的能力促使了几个新的类似物的合成，这些类似物能够绕过它们的主要限制，即它们不能被细胞激酶激活(磷酸化)。我们进行了两个方面的研究，并重点介绍了一些主要的发现：(1)成功地合成了N-甲基卡巴比丁异构体类似物，其中环丙烷环的融合位置和关键的3‘-OH基团都被重新定位，以便于被激动酶识别。这一方法导致由疱疹胸苷/胸苷酸激酶和细胞二磷酸激酶催化的所有三种代谢物(单磷酸、二磷酸和三磷酸)的形成增加了两倍；以及(2)发现了一种化合物D-Carba DT(碳环胸苷)，它被细胞胸苷激酶很好地磷酸化，有效地阻止了野生型和多药耐药HIV-1载体在培养细胞中的复制。N-甲卡巴夫定(N-MCT)已经获得许可，目标是作为抗卡波西肉瘤、单纯疱疹病毒1和2以及痘的抗病毒药物开发。最近发表在《抗病毒研究》上的一篇综述重点介绍了N-MCT的历史和发现。关于DNA弯曲的研究继续进行，完成了一项全面的研究，该研究描述了即将出版的含有南北两个对足的寡脱氧核苷酸的对比行为和退火性。

My laboratory continues to investigate the bicyclo[3.1.0]hexane template as a platform for the construction of novel conformationally locked carbocyclic nucleosides. We use these modified nucleosides with the purpose of (1) determining the conformational preferences of enzymes involved in the biochemistry of nucleosides, nucleotides, and oligonucleotides; and (2) developing selected compounds as possible antitumor/antiviral drugs based on our understanding of their biochemical mechanism of action. The application of this knowledge has been successfully applied to the design and synthesis of nucleoside analogues directed to precise therapeutic targets such as Kaposi sarcoma virus, HIV, herpes and more recently pox viruses. The effect of chemically synthesized North-methanocarba nucleoside 5'-triphosphates as delay chain terminators of HIV reverse transcriptase and their ability to overcome the excision mechanism of HIV resistance prompted the synthesis of several new analogues capable of circumventing their principal limitation, which is their inability to be activated (phosphorylated) by cellular kinases. Two lines of investigation have been pursued and some of the major findings are highlighted: (1) the successful synthesis of isomeric N-methanocarbathymidine analogues where both the fusion site of the cyclopropane ring and the critical 3'-OH group were relocated to facilitate recognition by kinases. This approach resulted in a 2-fold increase in the formation of all three metabolites (mono-, di- and triphosphates) catalyzed by the herpes thymidine/thymidylate kinase and the cellular diphosphate kinase; and (2) the discovery of a compound, D-Carba dT (carbocyclic thymidine), which is phosphorylated well enough by cellular thymidine kinase to be effective in blocking the replication of wild-type and multi-drug resistant HIV-1 vectors in cultured cells. North-methanocarbathymidine (N-MCT) has been licensed and it is targeted for development as an antiviral agent against Kaposi sarcoma, herpes simplex 1 and 2, and pox. A recent review published in Antiviral Research highlights the history and discovery of N-MCT. The studies on DNA bending continued with the completion of a comprehensive study describing the contrasting behavior and annealing properties of antipodal North- and South-containing olidodeoxynucleotides that will soon be published.