Massive Bioaccumulation and Self-Assembly of Phenazine Compounds in Live Cells
Massive Bioaccumulation and Self-Assembly of Phenazine Compounds in Live Cells
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DOI：
10.1002/advs.201500025
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发表时间：
2015-08-01
期刊：
影响因子：
15.1
通讯作者：
Rosania, Gus R.
中科院分区：
文献类型：
--
作者：
Min, Kyoung Ah;Rajeswaran, Walajapet G.;Rosania, Gus R.
氯法齐明是一种口服药物，在巨噬细胞中大量生物积累，形成具有纳米级超分子特征的膜结合胞内结构。在这里，从氯法齐明衍生的非那嗪化合物库被合成并测试了在细胞内积累和形成有序分子聚集体的能力。无论化学结构或理化性质如何，巨噬细胞的生物蓄积始终大于上皮细胞。显微镜下，一些自组装结构表现出明显的双衰减各向异性信号，从线偏振光的微分吸收可以看出，在非那嗪核心的峰值吸收波长。测量的各向异性远高于内源性细胞成分的背景各向异性，反映了有序非那嗪分子的凝聚不溶复合物的自组装。在非那嗪核心的r -亚氨基位置引入的化学变化导致化合物的生物积累行为以及由此产生的细胞内结构的形态和组织的特殊影响。除了氯法齐明之外，这些结果还证明了膜渗透的自组装，口服生物可利用的小分子构建块如何赋予细胞与其他天然细胞成分不同的具有化学，物理和功能特征的非自然结构元素。
Clofazimine is an orally administered drug that massively bioaccumulates in macrophages, forming membrane-bound intracellular structures possessing nanoscale supramolecular features. Here, a library of phenazine compounds derived from clofazimine is synthesized and tested for ability to accumulate and form ordered molecular aggregates inside cells. Regardless of chemical structure or physicochemical properties, bioaccumulation is consistently greater in macrophages than in epithelial cells. Microscopically, some self-assembled structures exhibit a pronounced, diattenuation anisotropy signal, evident by the differential absorption of linearly polarized light, at the peak absorbance wavelength of the phenazine core. The measured anisotropy is well above the background anisotropy of endogenous cellular components, refl ecting the self-assembly of condensed, insoluble complexes of ordered phenazine molecules. Chemical variations introduced at the R-imino position of the phenazine core lead to idiosyncratic effects on the compounds' bioaccumulation behavior as well as on the morphology and organization of the resulting intracellular structures. Beyond clofazimine, these results demonstrate how the self-assembly of membrane permeant, orally bioavailable small molecule building blocks can endow cells with unnatural structural elements possessing chemical, physical, and functional characteristics unlike those of other natural cellular components.