A Versatile Intermediate for the Preparation of C-Functionalized Azamacrocycles and Application to the Synthesis of the Potent Anti-HIV Agent (±)JM2936
A Versatile Intermediate for the Preparation of C-Functionalized Azamacrocycles and Application to the Synthesis of the Potent Anti-HIV Agent (±)JM2936
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一种用于制备 C 官能化氮杂大环化合物的多功能中间体及其在强效抗 HIV 药物 (±)JM2936 合成中的应用
DOI：
10.1021/jo951499w
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发表时间：
1996
影响因子：
3.6
通讯作者：
D. Thornton
中科院分区：
文献类型：
--
作者：
G. Bridger;R. Skerlj;A. S. Padmanabhan;D. Thornton
最近，我们报道了一系列新的双-四氮杂大环化合物的发现，如双环类化合物JM 2763（1）（图1），其表现出对人类免疫缺陷病毒1型（HIV-1）和2型（HIV-2）复制的有效和选择性抑制作用，具有独特的作用机制。1除了高抗病毒效力之外，在单个氮位置连接的四氮杂大环的二聚体由于其合成可及性而特别有吸引力的药物候选物。通过修改已建立的文献程序2，我们能够制备和报告一系列广泛的N-连接的双四氮杂大环化合物的结构-活性关系，其中大环的环尺寸从12-16元/环变化。3作为我们正在进行的理解这类化合物中有效抗HIV活性所需的结构特征的努力的一部分，我们研究了连接1，4，8，11-四氮杂环十四烷（[14] aneN 4，cyclam）环系统，本文报道了我们为实现这一目标所采用的合成方法，并以（（）JM 2936（2）的合成为例。据我们所知，JM 2936也是双-四氮杂大环的第一个例子，由于碳和氮位置上的环的不相同共价连接而不对称。5
Recently we reported the discovery of a novel series of bis-tetraazamacrocycles, such as the bicyclam JM2763 (1)(Figure 1), that exhibit potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication with a unique mechanism of action. 1 In addition to high antiviral potency, dimers of tetraazamacrocycles linked at a single nitrogen position are particularly attractive drug candidates due to their synthetic accessability. By modification of established literature procedures2 we were able to prepare and report the structure-activity relationship of an extensive series of N-linked bis-tetraazamacrocycles in which the macrocyclic ring size was varied from 12-16 members per ring. 3 As part of our ongoing efforts to understand the structural features required for potent anti-HIV activity in this class of compounds, we have investigated the effect of connecting the 1, 4, 8, 11-tetraazacyclotetradecane ([14] aneN4, cyclam) ring system (s) at carbon rather than nitrogen positions, 4 and this paper reports the synthetic methodology we have used to achieve this goal exemplified by the synthesis of (() JM2936 (2). To our knowledge, JM2936 is also the first example of a bis-tetraazamacrocycle that is unsymmetrical due to the nonidentical covalent connection of the rings at carbon and nitrogen positions. 5