SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PHENYLENEBIS(METHYLENE)-LINKED BIS-TETRAAZAMACROCYCLES THAT INHIBIT HIV REPLICATION - EFFECTS OF MACROCYCLIC RING SIZE AND SUBSTITUENTS ON THE AROMATIC LINKER
SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PHENYLENEBIS(METHYLENE)-LINKED BIS-TETRAAZAMACROCYCLES THAT INHIBIT HIV REPLICATION - EFFECTS OF MACROCYCLIC RING SIZE AND SUBSTITUENTS ON THE AROMATIC LINKER
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DOI：
10.1021/jm00002a019
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发表时间：
1995-01-20
影响因子：
7.3
通讯作者：
DECLERCQ, E
中科院分区：
文献类型：
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作者：
BRIDGER, GJ;SKERLJ, RT;DECLERCQ, E
我们之前已经描述了JM2763对几种人类免疫缺陷病毒1型（HIV-1）和2型（HIV-2）毒株的有效和选择性抑制作用，JM2763是1,4,8,11-四氮杂环（cyclam）环系统的正丙基连接二聚体。经过进一步的研究，我们还发现，结合芳香而不是脂肪连接导致类似物具有更高的抗病毒效力。原型JM3100 （19a，分离为八氯盐盐）含有连接环环的对苯基双（亚甲基）片段，在EC(50)'s处分别抑制了HIV-1 （IIIB）和HIV-2 （ROD）的复制，而在超过421 μ m的浓度下对MT-4细胞无毒。我们制备了一系列新的苯乙烯（亚甲基）连接的类似物，其中大环的大小从12到16个环成员不等。根据邻苯二烯（亚甲基）连接体（对或间）的取代，具有12-14环成员的大环的类似物具有亚微摩尔抗htv活性，但对MT-4细胞具有不同的细胞毒性。此外，虽然我们发现活性不需要相同的大环，但在19a中用一个等效的无环多胺取代其中一个环环导致抗hn效力大幅降低，清楚地确立了约束大环结构的重要性。制备了一系列短系列的过渡金属配合物，并对其进行了评价。低动力学稳定性的配合物，如双锌配合物，保留了与母体化合物相当的活性。最后，双环类似物的活性似乎对引入到连接体上的取代基的吸电子或供电子性质不敏感，但空间阻碍基团（如苯基）明显降低了活性。因此，已经确定了几种具有与19a相当的抗htv效力的类似物。
We have previously described the potent and selective inhibition of several strains of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by JM2763, an n-propyl-linked dimer of the 1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further investigation, we have also found that incorporating an aromatic rather than aliphatic linker leads to analogs with higher antiviral potency. The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC(50)'s of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 mu M. In order to identify the structural features of bis-tetraazamacrocycle s required for potent activity, we have prepared a novel series of phenylenebis(methylene)-linked analogs, in which the macrocyclic ring size was varied from 12 to 16 ring members. Depending upon the substitution of the phenylenebis(methylene) linker (para or meta), sub-micromolar anti-HTV activity was exhibited by analogs bearing macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4 cells. Furthermore, while we found that identical macrocyclic rings are not required for activity, substituting an acyclic polyamine equivalent for one of the cyclam rings in 19a resulted in a substantial reduction in anti-HN potency, clearly establishing the importance of the constrained macrocyclic structure. A short series of transition metal complexes of 19a were also prepared and evaluated. Complexes of low kinetic stability such as the bis-zinc complex retained activity comparable to that of the parent compound. Finally, the activity of bicyclam analogs appears to be insensitive to the electron-withdrawing or -donating properties of substituents introduced onto the linker, but sterically hindering groups such as phenyl markedly reduced activity. As a result, several analogs with anti-HTV potency comparable to that of 19a have been identified.