Bridger G J, Skerlj R T, Thornton D, Padmanabhan S, Martellucci S A, Henson G W, Abrams M J, Yamamoto N, De Vreese K, Pauwels R
Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania 19380.
J Med Chem. 1995 Jan 20;38(2):366-78. doi: 10.1021/jm00002a019.
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 EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM. In order to identify the structural features of bis-tetraazamacrocycles 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-HIV 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-HIV 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-HIV potency comparable to that of 19a have been identified.
我们之前曾报道过，1,4,8,11-四氮杂大环（环胺）环系统的正丙基连接二聚体JM2763对几种1型人类免疫缺陷病毒（HIV-1）和2型人类免疫缺陷病毒（HIV-2）具有强效且选择性的抑制作用。经过进一步研究，我们还发现引入芳香族而非脂肪族连接基团会产生具有更高抗病毒效力的类似物。原型化合物JM3100（19a，以八盐酸盐形式分离得到）含有连接环胺环的对亚苯基双（亚甲基）部分，分别以4.2和5.9 nM的半数有效浓度（EC50）抑制HIV-1（IIIB）和HIV-2（ROD）的复制，而在浓度超过421 μM时对MT-4细胞仍无毒。为了确定具有强效活性所需的双四氮杂大环的结构特征，我们制备了一系列新型的对亚苯基双（亚甲基）连接类似物，其中大环的环大小从12个环成员变化到16个环成员。根据对亚苯基双（亚甲基）连接基团的取代情况（对位或间位），具有12 - 14个环成员大环的类似物表现出亚微摩尔级的抗HIV活性，但对MT-4细胞具有不同的细胞毒性。此外，虽然我们发现活性并不需要相同的大环环，但用无环多胺类似物取代19a中的一个环胺环会导致抗HIV效力大幅降低，这清楚地表明了受限大环结构的重要性。还制备并评估了19a的一系列短链过渡金属配合物。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，双环胺类似物的活性似乎对引入连接基团上的取代基的吸电子或供电子性质不敏感，但空间位阻基团如苯基会显著降低活性。因此，已鉴定出几种抗HIV效力与19a相当的类似物。
