Krings Karina S, Wassenberg Tobias R, Cea-Medina Pablo, Schmitt Laura, Lechtenberg Ilka, Llewellyn Tanya R, Qin Nan, Gohlke Holger, Wesselborg Sebastian, Müller Thomas J J
Institute for Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.
Institute of Organic Chemistry and Macromolecular Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.
Molecules. 2024 Dec 23;29(24):6050. doi: 10.3390/molecules29246050.
(3-(pyrimidin-4-yl)-7-azaindoles) are synthetic hybrids of the naturally occurring alkaloids and and display a strong cytotoxic potential. We have recently shown that the novel derivative is highly cytotoxic in several lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells and predominantly targets cyclin-dependent kinases (CDKs). Here, we efficiently synthesized nine novel 2-aminopyridyl congeners (-), i.e., , using a one-pot borylation- coupling (MBSC) sequence, with eight of them bearing lipophilic alkoxy substituents of varying length, to systematically determine the influence of the alkoxy sidechain length on the biological activity. All the synthesized derivatives displayed a pronounced cytotoxic potential, with six compounds showing IC values in the nanomolar range. Derivatives - strongly induced apoptosis and activated caspases with rapid kinetics within 3-4 h in Jurkat leukemia and Ramos lymphoma cells. The induction of apoptosis by the most potent derivative was mediated by the intrinsic mitochondrial death pathway, as it was blocked in caspase-9 deficient and Apaf-1 knockdown Jurkat cells. However, as recently shown for derivative was able to induce apoptosis in the Jurkat cells overexpressing the antiapoptotic protein Bcl-2. Since tumor cells often inactivate the intrinsic mitochondrial apoptosis pathway (e.g., by overexpression of Bcl-2), these congeners represent promising therapeutic agents for overcoming therapeutic resistance.
（3-（嘧啶-4-基）-7-氮杂吲哚）是天然生物碱和的合成杂合物，具有很强的细胞毒性潜力。我们最近表明，这种新型衍生物在几种淋巴瘤和白血病细胞系以及原发性患者来源的淋巴瘤和白血病细胞中具有高度细胞毒性，并且主要靶向细胞周期蛋白依赖性激酶（CDK）。在此，我们使用一锅法硼化-偶联（MBSC）序列高效合成了九种新型2-氨基吡啶基同系物（-），即，其中八种带有不同长度的亲脂性烷氧基取代基，以系统地确定烷氧基侧链长度对生物活性的影响。所有合成的衍生物都显示出明显的细胞毒性潜力，六种化合物的IC值在纳摩尔范围内。衍生物-在Jurkat白血病细胞和Ramos淋巴瘤细胞中在3-4小时内以快速动力学强烈诱导凋亡并激活半胱天冬酶。最有效的衍生物诱导的凋亡是由内在的线粒体死亡途径介导的，因为它在半胱天冬酶-9缺陷和Apaf-1敲低的Jurkat细胞中被阻断。然而，正如最近对衍生物的研究表明，它能够在过表达抗凋亡蛋白Bcl-2的Jurkat细胞中诱导凋亡。由于肿瘤细胞经常使内在的线粒体凋亡途径失活（例如，通过Bcl-2的过表达），这些同系物代表了克服治疗抗性的有前途的治疗剂。
