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；(2)根据我们对其生化作用机制的了解，开发出可能的抗肿瘤/抗病毒药物。这一知识的应用已成功地应用于设计和合成核苷类似物，以精确治疗目标，如卡波西肉瘤病毒、艾滋病毒、疱疹和最近的痘病毒。化学合成的北甲碳核苷5'-三磷酸作为HIV逆转录酶延迟链终止子的作用及其克服HIV耐药性切除机制的能力促使合成了几种新的类似物，能够克服它们不能被细胞激酶激活（磷酸化）的主要限制。研究人员进行了两方面的研究，并突出了一些主要的发现：(1)成功合成了异分异构体n -甲烷氨基类似物，其中环丙烷环和关键的3'-OH基团的融合位点都被重新定位，以促进激酶的识别。这种方法导致由疱疹胸腺嘧啶/胸腺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2倍；(2)发现了一种化合物D-Carba dT（碳环胸腺嘧啶），该化合物可被细胞胸腺嘧啶激酶很好地磷酸化，从而有效阻断野生型和多重耐药HIV-1载体在培养细胞中的复制。北甲基氨基甲酸乙酯（N-MCT）已获得许可，作为一种针对卡波西肉瘤、单纯疱疹1型和2型以及痘的抗病毒药物正在开发中。最近发表在《抗病毒研究》上的一篇综述强调了N-MCT的历史和发现。关于DNA弯曲的研究继续进行，并完成了一项全面的研究，该研究描述了对跖的含北和含南的核苷脱氧核苷酸的对比行为和退火性质，该研究将很快发表。

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.