Kaya Busra, Smith Henry, Chen Yanbing, Azad Mahan Gholam, M Russell Tiffany, Richardson Vera, Bernhardt Paul V, Dharmasivam Mahendiran, Richardson Des R
Centre for Cancer Cell Biology and Drug Discovery, Griffith University Nathan Brisbane 4111 Queensland Australia
Department of Pathology and Bosch Institute, Molecular Pharmacology and Pathology Program, University of Sydney Sydney New South Wales Australia.
Chem Sci. 2024 Aug 15;15(37):15109-24. doi: 10.1039/d4sc04339a.
Innovative -acridine thiosemicarbazones (NATs) were designed along with their iron(iii), copper(ii), and zinc(ii) complexes. Lysosomal targeting was promoted by specifically incorporating the lysosomotropic Pgp substrate, acridine, into the thiosemicarbazone scaffold to maintain the tridentate N, N, S-donor system. The acridine moiety enables a significant advance in thiosemicarbazone design, since: (1) it enables tracking of the drugs by confocal microscopy using its inherent fluorescence; (2) it is lysosomotropic enabling lysosomal targeting; and (3) as acridine is a P-glycoprotein (Pgp) substrate, it facilitates lysosomal targeting, resulting in the drug overcoming Pgp-mediated resistance. These new -acridine analogues are novel, and this is the first time that acridine has been specifically added to the thiosemicarbazone framework to achieve the three important properties above. These new agents displayed markedly greater anti-proliferative activity against resistant Pgp-expressing cells than very low Pgp-expressing cells. The anti-proliferative activity of NATs against multiple Pgp-positive cancer cell-types (colon, lung, and cervical carcinoma) was abrogated by the third generation Pgp inhibitor, Elacridar, and also Pgp siRNA that down-regulated Pgp. Confocal microscopy demonstrated that low Pgp in KB31 (-Pgp) cells resulted in acridine's proclivity for DNA intercalation promoting NAT nuclear-targeting. In contrast, high Pgp in KBV1 (+Pgp) cells led to NAT lysosomal sequestration, preventing its nuclear localisation. High Pgp expression in KBV1 (+Pgp) cells resulted in co-localization of NATs with the lysosomal marker, LysoTracker™, that was significantly ( < 0.001) greater than the positive control, the di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) Zn(ii) complex, [Zn(DpC)]. Incorporation of acridine into the thiosemicarbazone scaffold led to Pgp-mediated transport into lysosomes to overcome Pgp-resistance.
设计了新型吖啶硫代氨基脲（NATs）及其铁（III）、铜（II）和锌（II）配合物。通过将溶酶体亲和性Pgp底物吖啶特异性地引入硫代氨基脲支架中以维持三齿N、N、S供体体系，促进了溶酶体靶向作用。吖啶部分使硫代氨基脲的设计有了显著进展，因为：（1）它能利用其固有荧光通过共聚焦显微镜追踪药物；（2）它具有溶酶体亲和性，能够实现溶酶体靶向；（3）由于吖啶是一种P-糖蛋白（Pgp）底物，它有助于溶酶体靶向，从而使药物克服Pgp介导的耐药性。这些新型吖啶类似物是新颖的，这是首次将吖啶特异性添加到硫代氨基脲框架中以实现上述三个重要特性。这些新药剂对表达耐药Pgp的细胞显示出比对表达极低Pgp的细胞明显更强的抗增殖活性。NATs对多种Pgp阳性癌细胞类型（结肠癌、肺癌和宫颈癌）的抗增殖活性被第三代Pgp抑制剂艾拉司群以及下调Pgp的Pgp siRNA消除。共聚焦显微镜显示，KB31（-Pgp）细胞中低水平的Pgp导致吖啶倾向于插入DNA，促进NAT的核靶向。相反，KBV1（+Pgp）细胞中高水平的Pgp导致NAT被溶酶体隔离，阻止其核定位。KBV1（+Pgp）细胞中高Pgp表达导致NATs与溶酶体标记物LysoTracker™共定位，其共定位程度显著（<0.001）高于阳性对照二-2-吡啶酮-4-环己基-4-甲基-3-硫代氨基脲（DpC）锌（II）配合物[Zn（DpC）]。将吖啶引入硫代氨基脲支架导致Pgp介导的转运进入溶酶体以克服Pgp耐药性。
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